JP7041140B2 - Substituted 6-membered aryl or heteroaryl nicotinic acetylcholine receptor allosteric regulator - Google Patents
Substituted 6-membered aryl or heteroaryl nicotinic acetylcholine receptor allosteric regulator Download PDFInfo
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- JP7041140B2 JP7041140B2 JP2019520682A JP2019520682A JP7041140B2 JP 7041140 B2 JP7041140 B2 JP 7041140B2 JP 2019520682 A JP2019520682 A JP 2019520682A JP 2019520682 A JP2019520682 A JP 2019520682A JP 7041140 B2 JP7041140 B2 JP 7041140B2
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- Prior art keywords
- cyclopropyl
- trans
- benzenesulfonamide
- alkyl
- propane
- Prior art date
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- 125000001072 heteroaryl group Chemical group 0.000 title claims description 50
- 125000003118 aryl group Chemical group 0.000 title claims description 43
- 230000003281 allosteric effect Effects 0.000 title description 7
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 title 1
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 215
- -1 NR 7 R 8 Chemical group 0.000 claims description 116
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- 229910052736 halogen Inorganic materials 0.000 claims description 45
- 150000002367 halogens Chemical class 0.000 claims description 42
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 38
- 239000003814 drug Substances 0.000 claims description 37
- 201000000980 schizophrenia Diseases 0.000 claims description 36
- 208000024827 Alzheimer disease Diseases 0.000 claims description 34
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 33
- 108700006085 alpha7 Nicotinic Acetylcholine Receptor Proteins 0.000 claims description 33
- 102000047725 alpha7 Nicotinic Acetylcholine Receptor Human genes 0.000 claims description 33
- 125000001424 substituent group Chemical group 0.000 claims description 31
- 208000018737 Parkinson disease Diseases 0.000 claims description 29
- 125000000623 heterocyclic group Chemical group 0.000 claims description 28
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 25
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 24
- 208000010877 cognitive disease Diseases 0.000 claims description 23
- 239000003112 inhibitor Substances 0.000 claims description 23
- 230000000694 effects Effects 0.000 claims description 19
- 229940124597 therapeutic agent Drugs 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 16
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 16
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 15
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 13
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 13
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 102000010909 Monoamine Oxidase Human genes 0.000 claims description 9
- 108010062431 Monoamine oxidase Proteins 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000000544 cholinesterase inhibitor Substances 0.000 claims description 8
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
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- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229910052710 silicon Inorganic materials 0.000 claims description 7
- 230000000561 anti-psychotic effect Effects 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 5
- 125000001425 triazolyl group Chemical group 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- GZJAMVQTRMYNFV-DLBZAZTESA-N 4-[(1R,3R)-2,2-difluoro-3-[4-(3-fluorophenyl)pyrimidin-2-yl]cyclopropyl]benzenesulfonamide Chemical compound FC1([C@H]([C@@H]1C1=NC=CC(=N1)C1=CC(=CC=C1)F)C1=CC=C(C=C1)S(=O)(=O)N)F GZJAMVQTRMYNFV-DLBZAZTESA-N 0.000 claims description 2
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- 238000002560 therapeutic procedure Methods 0.000 claims description 2
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- 150000008331 benzenesulfonamides Chemical class 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 171
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 50
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- 239000000556 agonist Substances 0.000 description 35
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
- 238000000034 method Methods 0.000 description 33
- 238000010828 elution Methods 0.000 description 32
- 229920006395 saturated elastomer Polymers 0.000 description 29
- 238000012360 testing method Methods 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 239000011780 sodium chloride Substances 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000000284 extract Substances 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- 239000005557 antagonist Substances 0.000 description 23
- 238000006243 chemical reaction Methods 0.000 description 23
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 229920002401 polyacrylamide Polymers 0.000 description 21
- 238000010898 silica gel chromatography Methods 0.000 description 21
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 18
- 229960004373 acetylcholine Drugs 0.000 description 18
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 16
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 16
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- 235000011152 sodium sulphate Nutrition 0.000 description 16
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Description
本開示は、α7nAChRの調節剤として有用な化合物、そのような化合物を含む組成物、及び疾患、特にアルツハイマー病、パーキンソン病及び統合失調症における認知機能障害などの中枢神経系の障害を予防、治療又は改善するためのそのような化合物の使用に関する。 The present disclosure prevents and treats compounds useful as regulators of α7nAChR, compositions containing such compounds, and disorders of the central nervous system such as cognitive dysfunction in Alzheimer's disease, Parkinson's disease and schizophrenia. Or with respect to the use of such compounds to improve.
α7nAChRは、Ca2+に対する高透過率を有する急速脱感作リガンド依存性イオンチャンネルである。ヒト脳において、α7nAChRは、認知に関連する領域である大脳皮質及び海馬で高度に発現される(例えば、Breese et al. J. Comp. Neurol. (1997) 387:385-398を参照する。)。ニューロンにおいて、α7nAChRは、シナプス前及びシナプス後の両方の構造に局在化しており、その受容体の活性化は、神経伝達物質放出、神経細胞の興奮性、及び細胞内シグナル伝達を調節することができる(例えば、Frazier et al. J. Neurosci. (1998) 18:1187-1195を参照する。)。 α7nAChR is a rapidly desensitizing ligand-dependent ion channel with high permeability to Ca 2+ . In the human brain, α7nAChR is highly expressed in the cognitive regions of the cerebral cortex and hippocampus (see, eg, Breese et al. J. Comp. Neurol. (1997) 387: 385-398). .. In neurons, α7nAChR is localized to both presynaptic and postsynaptic structures, and its receptor activation regulates neurotransmitter release, neuronal excitability, and intracellular signaling. (See, for example, Frazier et al. J. Neurosci. (1998) 18: 1187-1195).
認識機能障害は、アルツハイマー病(AD)、統合失調症及びパーキンソン病のような多くの神経疾患及び精神疾患において一般的であり、そして、コリン作動性シグナル伝達における機能不全がこれらの疾患の認知機能障害に関与している(例えばFrancis et al. J. Neurol. Neurosurg. Psychiatry (1999) 66:137-147を参照する。)。例えば、ADにおける病因の主たる特徴は、前脳基底部核におけるコリン作動性ニューロンの喪失であるが、アセチルコリンエステラーゼの阻害を介したコリン作動性伝達の増加が、ADの認知的徴候に対する標準治療である。α7nAChRにより特化すると、α7nAChRの部分作動薬であるエンセニクリンがアルツハイマー病における認知を改善することが最近示されている(例えば、Moebius H et al, 67th Annual Meeting. Am. Acad. Neurol. (AAN) 2015, Abst P7.100を参照する。)。統合失調症の病因におけるα7nAChRを示唆する証拠が、統合失調症患者の脳での神経細胞α7nAChRの低下した発現を示す試験、並びに統合失調症患者が、自己治療の1形態と考えられている喫煙頻度が高いという知見からもたらされている。さらに、α7nAChRタンパク質の発現に影響するα7nAChRをコードする遺伝子のプロモーター領域における変異体であるCHRNA7が、統合失調症の徴候に関連している(例えば、Sinkus et al. Neuropharmacology (2015) 96:274-288を参照する。)。さらに、臨床試験からの累積証拠が、α7nAChRの作動薬での活性化が、認知に対して有益な効果を有し得ることを示している(例えばKeefe et al. Neuropsychopharmacology (2015) 40:3053-3060及びBertrand et al. Pharmacology Reviews (2015) 67:1025-1073を参照する。)。従って、α7nAChRを標的とすることは、各種認知障害に関連する認知機能障害の治療のための治療戦略を代表する。 Cognitive dysfunction is common in many neurological and psychiatric disorders such as Alzheimer's disease (AD), schizophrenia and Parkinson's disease, and dysfunction in cholinergic signaling is the cognitive function of these disorders. Involved in the disorder (see, eg, Francis et al. J. Neurol. Neurosurg. Psychiatry (1999) 66: 137-147). For example, the main etiology in AD is the loss of cholinergic neurons in the basal forebrain nucleus, but increased cholinergic transmission through inhibition of acetylcholinesterase is the standard treatment for cognitive signs of AD. be. Specialization by α7nAChR has recently shown that encenicline, a partial agonist of α7nAChR, improves cognition in Alzheimer's disease (eg, Moevius Het al, 67th Annual Meeting. Am. Acad. Neurol. (AAN)). 2015, see Abst P7.100). Evidence suggesting α7nAChR in the etiology of schizophrenia is a study showing decreased expression of neurons α7nAChR in the brain of schizophrenic patients, as well as smoking in which schizophrenic patients are considered a form of self-treatment. It comes from the finding that it is frequent. In addition, CHRNA7, a variant in the promoter region of the gene encoding α7nAChR that affects the expression of the α7nAChR protein, is associated with signs of schizophrenia (eg, Sinkus et al. Neuropharmacology (2015) 96: 274-). 288.). In addition, cumulative evidence from clinical trials has shown that activation of α7nAChR with agonists can have beneficial effects on cognition (eg, Keefe et al. Neuropsychopharmacology (2015) 40: 3053-). 3060 and Bertrand et al. Pharmacology Reviews (2015) 67: 1025-1073). Therefore, targeting α7nAChR represents a therapeutic strategy for the treatment of cognitive dysfunction associated with various cognitive deficits.
パーキンソン病(PD)は、振戦、運動緩徐、強直及び姿勢反射障害のような運動機能における進行性欠陥を特徴とする神経変性疾患である。その疾患に関連する病理所見は、黒質におけるドーパミン作動性ニューロンの変性であり、それによって、線条体におけるドーパミン作用の喪失が生じる。L-DOPAは、PDにおける運動症状の現行の標準治療である。しかしながら、PD患者でのL-DOPAによる慢性治療も、L-DOPA療法の副作用である運動障害を誘発する。新たな系統の証拠が、α7nAChRの活性化によっていくつかの動物モデルで運動障害が急性的に緩和されることを示している(例えばZhang et al. J. Pharmacol. Exp. Ther. (2014) 351:25-32を参照する。)。さらに、蓄積された証拠から、α7nAChR作動薬による前処置が、黒質線条体ニューロンでの神経変性に対する保護を提供し得ることが明らかになっており、それはα7活性化が疾患修飾特性も有し得ることを示唆している(例えばSuzuki et al. J. Neurosci. Res. (2013) 91:462-471を参照する。)。全体的に見て、α7nAChRは、疾患進行の改善及び運動障害の管理の両方についての魅力的な標的である。 Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive defects in motor function such as tremor, slow motion, ankylosis and postural instability. The pathological finding associated with the disease is the degeneration of dopaminergic neurons in the substantia nigra, which results in the loss of dopaminergic action in the striatum. L-DOPA is the current standard of care for motor symptoms in PD. However, chronic treatment with L-DOPA in PD patients also induces movement disorders, which is a side effect of L-DOPA therapy. Evidence of a new strain has shown that activation of α7nAChR acutely alleviates movement disorders in some animal models (eg Zhang et al. J. Pharmacol. Exp. Ther. (2014) 351). : See 25-32.). In addition, accumulated evidence reveals that pretreatment with α7nAChR agonists may provide protection against neurodegeneration in substantia nigra striatal neurons, which is that α7 activation also has disease-modifying properties. (See, for example, Suzuki et al. J. Neurosci. Res. (2013) 91: 462-471). Overall, α7nAChR is an attractive target for both improving disease progression and managing movement disorders.
中枢神経系での発現に加えて、α7nAChRは、マクロファージ、単球、樹状細胞、並びにB細胞及びT細胞を含む末梢免疫細胞で広く発現される(例えばRosas-Ballina et al. Science (2011) 334:98-101を参照する。)。末梢α7nAChRの活性化が、コリン作動性抗炎症経路を介した炎症性サイトカイン類の放出を阻害するのに必須である(例えばWang et al. Nature (2003) 421:384-388を参照する。)。従って、α7nAChRは、関節リウマチ及びアテローム性動脈硬化のようないくつかの炎症疾患の標的となり得る(例えば、WJ de Jonge et al. British J. Pharmacol. (2007)151:915-929を参照する。)。 In addition to expression in the central nervous system, α7nAChR is widely expressed in macrophages, monocytes, dendritic cells, and peripheral immune cells including B and T cells (eg, Rosas-Ballina et al. Science (2011)). 334: 98-101.). Activation of peripheral α7nAChR is essential for inhibiting the release of inflammatory cytokines via the cholinergic anti-inflammatory pathway (see, eg, Wang et al. Nature (2003) 421: 384-388). .. Therefore, α7nAChR can be a target for some inflammatory diseases such as rheumatoid arthritis and atherosclerosis (see, eg, WJ de Jonge et al. British J. Pharmacol. (2007) 151: 915-929. ).
近年、α7選択的ポジティブアロステリック調節剤(PAM)が、AD、PD及び統合失調症での認知機能障害並びにL-DOPA誘発運動障害及び炎症を治療するための治療アプローチとして提案されている。内因性作動薬とは無関係にチャンネルを活性化するα7作動薬とは対照的に、PAMは、神経伝達の時間的および空間的完全性を乱すことなく、内因性作動薬の効力を高める。二種類のα7PAM、I型およびII型があり、それらは調節の機能特性に基づいて異なっている。I型PAM(例えば、NS1738、例えば、Timmermann et al. J. Pharmacol. Exp. Ther. (2007) 323:294-307を参照する。)は主として、受容体脱感作にはほとんど効果なくピーク電流に影響するが、II型PAM(例えば、PNU120596、例えばHurst et al. J. Neurosci. (2005) 25:4396-4405を参照する。)は、受容体の脱感作を顕著に遅延させる。さらに、α7nAChR PAMは、恐らくは受容体の非保存領域への結合を介して、関連するチャンネル標的に対して改善された選択性を有し得る。 In recent years, α7 selective positive allosteric regulators (PAMs) have been proposed as therapeutic approaches for treating cognitive dysfunction and L-DOPA-induced movement disorders and inflammation in AD, PD and schizophrenia. In contrast to the α7 agonist, which activates channels independently of the endogenous agonist, PAM enhances the efficacy of the endogenous agonist without disturbing the temporal and spatial integrity of neurotransmission. There are two types of α7PAM, type I and type II, which differ based on the functional characteristics of the regulation. Type I PAMs (see, eg, NS1738, eg, Timmermann et al. J. Pharmacol. Exp. Ther. (2007) 323: 294-307) have little effect on receptor desensitization and peak currents. However, type II PAM (see, eg, PNU120596, eg, Hurst et al. J. Neurosci. (2005) 25: 4396-4405) significantly delays receptor desensitization. In addition, α7nAChR PAM may have improved selectivity for the associated channel target, presumably through binding of the receptor to the non-conserved region.
本発明は、α7nAChRのポジティブアロステリック調節を示す新たな種類の化合物に関する。 The present invention relates to a novel class of compounds exhibiting positive allosteric regulation of α7nAChR.
本開示は、新規な式Iの化合物及び薬学的に許容されるその塩に関する。これらの化合物は、α7nAChRの調節、疾患、特にはアルツハイマー病、パーキンソン病及び統合失調症における認知機能障害のような中枢神経系の障害の予防、治療若しくは改善において化合物又は薬学的に許容されるその塩(適切な場合)として、及び/又は医薬組成物成分として有用であり得る。医薬組成物成分として、これらの化合物及びそれらの塩は、主たる活性治療剤であることができ、適切な場合、限定されるものではないが、アセチルコリンエステラーゼ阻害剤、NMDA受容体拮抗薬、β-セクレターゼ阻害剤、M4mAChR作動薬又はPAM、mGluR2拮抗薬又はNAM又はPAM、5-HT6拮抗薬、ヒスタミンH3受容体拮抗薬、PDE4阻害剤、PDE9阻害剤、HDAC6阻害剤、抗精神病薬、MAO-B阻害剤及びレボドパを含む他の治療剤と組み合わせることができる。 The present disclosure relates to a novel compound of formula I and a pharmaceutically acceptable salt thereof. These compounds are compounds or pharmaceutically acceptable thereof in the regulation of α7nAChR, the prevention, treatment or amelioration of disorders of the central nervous system such as cognitive dysfunction in Alzheimer's disease, Parkinson's disease and schizophrenia. It may be useful as a salt (where appropriate) and / or as a component of a pharmaceutical composition. As components of the pharmaceutical composition, these compounds and salts thereof can be the primary active therapeutic agent and, where appropriate, but not limited to, acetylcholine esterase inhibitors, NMDA receptor antagonists, β-. Secretase inhibitor, M4mAChR agonist or PAM, mGluR2 antagonist or NAM or PAM, 5-HT6 antagonist, histamine H3 receptor antagonist, PDE4 inhibitor, PDE9 inhibitor, HDAC6 inhibitor, antipsychotic drug, MAO-B It can be combined with other therapeutic agents including inhibitors and levodopa.
1態様において、本発明は、式Iの化合物又は薬学的に許容されるその塩に関するものであり、
式中、
Xは、
X is
から選択され、
Yは、4個の置換基であり、それぞれ独立にH、(C1-C4)アルキル、ハロゲン及びOHから選択され、ここで、前記アルキルは1以上のハロゲン又はOHで置換されていても良く;
Aは、6員アリール又はヘテロアリール環であり、それぞれ独立にOH、オキソ、アミノ、アミド、カルボキシル、ケト、シアノ、アルコキシ、S(O)m-アルキル、ハロゲン、アミノアルキル、ヒドロキシアルキル、アルキル、シクロアルキル、アルキニル、アリール、ヘテロアリール及び複素環から選択される1~4個のR基で置換され、ここで、前記アミノ、アミド、カルボキシル、ケト、アルコキシ、S(O)m-アルキル、アミノアルキル、ヒドロキシアルキル、アルキル、シクロアルキル、アルキニル、アリール、ヘテロアリール及び複素環は、独立にハロゲン、OH、オキソ、CF3、OCF3、CN、(C1-C6)アルキル、O(C1-C4)アルキル、S(O)m-(C1-C4)アルキル、C=O(C1-C4)アルキル、(C=O)NR7R8、(C=O)OR7、(C2-C4)アルキニル、(C3-C6)シクロアルキル、O(C3-C6)シクロアルキル、C=O(C3-C6)シクロアルキル、アリール、ヘテロアリール及び複素環から選択される1以上の置換基で置換されていても良く、ここで、前記アルキル、アリール、ヘテロアリール及び複素環は、独立に1以上のハロゲン、CF3、OH及びオキソで置換されていても良く;
R1はH又は(C1-C4)アルキルであり;
R2はH又は(C1-C4)アルキルであり;
R3は、H、ハロゲン、Si(CH3)3又は(C1-C4)アルキルであり、ここで、前記アルキルは、1以上のハロゲンで置換されていても良く;
R4は、H、ハロゲン又は(C1-C4)アルキルであり、ここで、前記アルキルは、1以上のハロゲンで置換されていても良く;
又は、R3及びR4が一緒になって、シクロプロピル、シクロブチル、シクロペンチル又はシクロヘキシル環を形成していても良く、ここで、前記環は、独立にOH、ハロゲン又は(C1-C4)アルキルから選択される1以上の置換基で置換されていても良く;
R5はH又は(C1-C4)アルキルであり;
R6はH又は(C1-C4)アルキルであり;
R7及びR8は、独立にH、(C1-C6)アルキル、シクロアルキル、アリール、ヘテロアリール及び複素環から選択され、ここで、前記アルキル、シクロアルキル、アリール、ヘテロアリール及び複素環は、独立にハロゲン、OH、CF3、(C1-C4)アルキル、O(C1-C4)アルキル、シクロアルキル、CN、アリール、ヘテロアリール及び複素環から選択される1以上の置換基で置換されていても良く、ここで、前記アルキル、シクロアルキル、アリール、ヘテロアリール及び複素環は、独立にハロゲン、OH、CF3、(C1-C4)アルキル、O(C1-C4)アルキル、CNから選択される1以上の置換基で置換されていても良く;
RaはH又は(C1-C4)アルキルであり;
Rbは、H又は(C1-C4)アルキルであり;そして
mは0、1又は2である。
Selected from
Y is four substituents, each independently selected from H, (C1 - C4 ) alkyl, halogen and OH, where the alkyl is substituted with one or more halogens or OH. well;
A is a 6-membered aryl or heteroaryl ring, which is independently OH, oxo, amino, amide, carboxyl, keto, cyano, alkoxy, S (O) m -alkyl, halogen, aminoalkyl, hydroxyalkyl, alkyl, respectively. Substituted with 1 to 4 R groups selected from cycloalkyl, alkynyl, aryl, heteroaryl and heterocycles, wherein the amino, amide, carboxyl, keto, alkoxy, S (O) m -alkyl, amino Alkyl, hydroxyalkyl, alkyl, cycloalkyl, alkynyl, aryl, heteroaryl and heterocycles are independently halogen, OH, oxo, CF 3 , OCF 3 , CN, (C 1 -C 6 ) alkyl, O (C 1 ). -C 4 ) alkyl, S (O) m- (C 1 -C 4 ) alkyl, C = O (C 1 -C 4 ) alkyl, (C = O) NR 7 R 8 , (C = O) OR 7 , ( C2 - C4 ) alkynyl, (C3 - C6) cycloalkyl, O (C3 - C6) cycloalkyl , C = O (C3 - C6 ) cycloalkyl, aryl, heteroaryl and complex It may be substituted with one or more substituents selected from the ring, wherein the alkyl, aryl, heteroaryl and heterocycle are independently substituted with one or more halogens, CF 3 , OH and oxo. May;
R 1 is H or (C 1 -C 4 ) alkyl;
R2 is H or (C1 - C4 ) alkyl;
R 3 is an H, halogen, Si (CH 3 ) 3 or (C1 -C 4 ) alkyl, where the alkyl may be substituted with one or more halogens;
R4 is H, a halogen or a (C1- C4 ) alkyl, where the alkyl may be substituted with one or more halogens;
Alternatively, R 3 and R 4 may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring, where the rings are independently OH, halogen or (C1 - C4 ). It may be substituted with one or more substituents selected from alkyl;
R 5 is H or (C 1 -C 4 ) alkyl;
R 6 is H or (C 1 -C 4 ) alkyl;
R 7 and R 8 are independently selected from H, (C1 - C 6 ) alkyl, cycloalkyl, aryl, heteroaryl and heterocycles, wherein said alkyl, cycloalkyl, aryl, heteroaryl and heterocycle. Is independently one or more substitutions selected from halogen, OH, CF 3 , (C1 - C4 ) alkyl, O (C1 - C4 ) alkyl, cycloalkyl, CN, aryl, heteroaryl and heterocycles. It may be substituted with a group, wherein the alkyl, cycloalkyl, aryl, heteroaryl and heterocycle are independently halogen, OH, CF 3 , (C1 - C4 ) alkyl, O (C1 - C4). C 4 ) It may be substituted with one or more substituents selected from alkyl and CN;
Ra is H or (C1 - C4 ) alkyl;
R b is H or (C 1 -C 4 ) alkyl; and m is 0, 1 or 2.
本発明は、本発明の化合物を含む医薬組成物及びそのような医薬組成物の製造方法も含む。本発明はさらに、アルツハイマー病、パーキンソン病及び統合失調症に関連する認知機能障害を予防、治療又は改善する方法を含む。 The present invention also includes a pharmaceutical composition containing the compound of the present invention and a method for producing such a pharmaceutical composition. The present invention further includes methods for preventing, treating or ameliorating cognitive dysfunction associated with Alzheimer's disease, Parkinson's disease and schizophrenia.
本発明の他の実施形態、態様及び特徴は、下記の説明、実施例及び添付の特許請求の範囲に記載されているか、それらから明らかになろう。 Other embodiments, embodiments and features of the invention are described or will be apparent from the following description, examples and the appended claims.
本発明は、上記の式Iの化合物及び薬学的に許容されるその塩を含む。式Iの化合物は、α7nAChRのポジティブアロステリック調節剤である。 The present invention includes compounds of formula I above and pharmaceutically acceptable salts thereof. The compound of formula I is a positive allosteric regulator of α7nAChR.
本発明の第1の実施形態において、Xは
であり;他の基は上記一般式で提供の通りである。 The other groups are as provided by the above general formula.
本発明の第2の実施形態において、YはHであり、そして、他の基は、上記一般式で提供の通りであるか、第1の実施形態で提供の通りである。 In a second embodiment of the invention, Y is H, and the other groups are as provided in the general formula above or as provided in the first embodiment.
本発明の第3の実施形態において、Aは、ピリジン、ピリミジン、フェニル、ピリダジン、ピラジン、トリアジン、ピリジノン、ピリミジノン、ピラジノン及びピリダジノンから選択され、それぞれ独立にハロゲン、CN、(C1-C6)アルキル、O(C1-C6)アルキル、NR7R8、(C3-C6)シクロアルキル、アリール、ヘテロアリール及び複素環から選択される1~2個のR基によって置換され、ここで、前記アルキル、NR7R8、(C3-C6)シクロアルキル、アリール、ヘテロアリール及び複素環は、独立にハロゲン、CN、(C1-C6)アルキル、(C=O)O(C1-C4)アルキル及びフェニルから選択される1以上の置換基によって置換されていても良く、ここで、前記アルキルは、1以上のハロゲンによって置換されていても良く;そして、他の基は、上記一般式で提供の通りであるか、第1若しくは第2の実施形態で提供の通りである。 In a third embodiment of the invention, A is selected from pyridine, pyrimidine, phenyl, pyridazine, pyrazine, triazine, pyridinone, pyrimidinone, pyrazinone and pyridadinone, respectively, independently halogen, CN, (C 1 -C 6 ). Substituent with 1-2 R groups selected from alkyl, O (C 1 -C 6 ) alkyl, NR 7 R 8 , (C 3 -C 6 ) cycloalkyl, aryl, heteroaryl and heterocycles. The alkyl, NR 7 R 8 , (C 3 -C 6 ) cycloalkyl, aryl, heteroaryl and heterocycle are independently halogen, CN, (C 1 -C 6 ) alkyl, (C = O) O. (C 1 -C 4 ) May be substituted with one or more substituents selected from alkyl and phenyl, where the alkyl may be substituted with one or more halogens; and the other. The group is as provided in the above general formula, or as provided in the first or second embodiment.
本発明の第4の実施形態において、R5、R6、Ra及びRbは独立にH又はメチルであり、他の基は上記一般式で提供の通りであるか、第1、第2若しくは第3の実施形態で提供の通りである。 In the fourth embodiment of the present invention, R 5 , R 6 , Ra and R b are independently H or methyl, and the other groups are as provided by the above general formula, or the first, second. Or as provided in the third embodiment.
本発明の第5の実施形態において、R3及びR4は独立に、H、F、Si(CH3)3又はメチルであり、そして、他の基は上記一般式で提供の通りであるか、第1~第4の実施形態で提供の通りである。 In a fifth embodiment of the invention, are R 3 and R 4 independently H, F, Si (CH 3 ) 3 or methyl, and are the other groups as provided by the general formula above? , As provided in the first to fourth embodiments.
本発明の第6の実施形態において、R7及びR8は、独立にH、(C1-C6)アルキル、シクロペンチル及びフェニルから選択され、ここで、前記アルキル及びフェニルは、ハロゲン又はフェニルで置換されていても良く、そして、他の基は、上記一般式で提供の通りであるか、第1~第5の実施形態で提供の通りである。 In a sixth embodiment of the invention, R 7 and R 8 are independently selected from H, (C1 - C 6 ) alkyl, cyclopentyl and phenyl, where the alkyl and phenyl are halogen or phenyl. It may be substituted and the other groups are as provided in the above general formula or as provided in the first to fifth embodiments.
本発明の第7の実施形態において、本発明の化合物は、下記式を有するか、薬学的に許容されるその塩であり、
式中、
Aは、ピリジン、ピリミジン、フェニル、ピリダジン及びピラジンから選択され、それぞれ、(C1-C6)アルキル、O(C1-C6)アルキル、NR7R8、(C3-C6)シクロアルキル、アリール、ヘテロアリール及び複素環から選択される1個のR基で置換され、ここで、それぞれは、独立にハロゲン、CF3、CN、(C1-C4)アルキル、(C=O)O(C1-C4)アルキル及びフェニルから選択される1以上の置換基で置換されていても良く;
R3はH又はSi(CH3)3であり;
R4はHであり;そして、
R7及びR8は、独立にH、(C1-C6)アルキル、(C3-C6)シクロアルキル、アリール、ヘテロアリール及び複素環から選択され、ここで、各アルキル、シクロアルキル、アリール、ヘテロアリール及び複素環は、独立にハロゲン及びフェニルから選択される1以上の置換基で置換されていても良い。
During the ceremony
A is selected from pyridine, pyrimidine, phenyl, pyridazine and pyrazine, (C 1 -C 6 ) alkyl, O (C 1 -C 6 ) alkyl, NR 7 R 8 and (C 3 -C 6 ) cyclo, respectively. Substituted with one R group selected from alkyl, aryl, heteroaryl and heterocycles, where each is independently halogen, CF 3 , CN, (C 1 -C 4 ) alkyl, (C = O). ) O (C1- C4 ) May be substituted with one or more substituents selected from alkyl and phenyl;
R 3 is H or Si (CH 3 ) 3 ;
R4 is H; and
R 7 and R 8 are independently selected from H, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, aryl, heteroaryl and heterocycle, where each alkyl, cycloalkyl, Aryls, heteroaryls and heterocycles may be substituted with one or more substituents independently selected from halogens and phenyls.
本発明の第8の実施形態において、本発明の化合物は、式(Ia)を有するか薬学的に許容されるその塩であり、
Aは、ピリジン、ピリミジン、フェニル、ピリダジン及びピラジンから選択され、それぞれ、(C1-C6)アルキル、O(C1-C6)アルキル、NR7R8、シクロブチル、シクロペンチル、フェニル、ピリジニル、モルホリニル、イミダゾリル、ピラゾリル、オキサジアゾリル、ピロリジニル、ピペラジニル、トリアゾリル及びテトラヒドロピラニルから選択される1個のR基で置換されており、ここで、それぞれは、独立にハロゲン、CF3、CN、(C1-C4)アルキル、(C=O)O(C1-C4)アルキル及びフェニルから選択される1以上の置換基で置換されていても良く;
R3はH又はSi(CH3)3であり;
R4はHであり;そして
R7及びR8は、独立にH、(C1-C6)アルキル、シクロペンチル及びフェニルから選択され、ここで、各アルキル、シクロペンチル及びフェニルは、独立にハロゲン及びフェニルから選択される1以上の置換基で置換されていても良い。
In an eighth embodiment of the invention, the compound of the invention is a salt thereof having formula (Ia) or pharmaceutically acceptable thereof.
A is selected from pyridine, pyrimidine, phenyl, pyridazine and pyrazine, respectively (C 1 -C 6 ) alkyl, O (C 1 -C 6 ) alkyl, NR 7 R 8 , cyclobutyl, cyclopentyl, phenyl, pyridinyl, respectively. It is substituted with one R group selected from morpholinyl, imidazolyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, piperazinyl, triazolyl and tetrahydropyranyl, where each is independently halogen, CF 3 , CN, (C 1 ). -C 4 ) Alkyl, (C = O) O (C1 - C 4 ) Alkyl and may be substituted with one or more substituents selected from phenyl;
R 3 is H or Si (CH 3 ) 3 ;
R 4 is H; and R 7 and R 8 are independently selected from H, (C1 - C 6 ) alkyl, cyclopentyl and phenyl, where each alkyl, cyclopentyl and phenyl are independently halogen and. It may be substituted with one or more substituents selected from phenyl.
本発明はまた、下記の例示的化合物:
4-{トランス-2-[6-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[2-(モルホリン-4-イル)ピリミジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
4-[トランス-2-(6-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド;
4-[トランス-2-(5-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド;
4-{トランス-2-[4-(プロパン-2-イル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(ピロリジン-1-イル)ピリジン-3-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[3-(5-メチル-1,2,4-オキサジアゾール-3-イル)フェニル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[2-(プロパン-2-イル)ピリジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
4-[(1R,3R)-2,2-ジメチル-3-{4-[5-(トリフルオロメチル)ピリジン-3-イル]ピリミジン-2-イル}シクロプロピル]ベンゼンスルホンアミド;
4-{トランス-2-[4-(3-フルオロフェニル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-(トランス-2-{4-[5-(トリフルオロメチル)ピリジン-3-イル]ピリミジン-2-イル}シクロプロピル)ベンゼンスルホンアミド;
4-{トランス-2-[6-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[4-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[5-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-[トランス-2-(6-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド;
4-{トランス-2-[5-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[5-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[3-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(1H-ピラゾール-1-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(テトラヒドロ-2H-ピラン-4-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[4-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-[トランス-2-(6-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド;
4-[トランス-2-(5-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド;
4-{2-[6-(プロパン-2-イル)ピリジン-3-イル]-3-(トリメチルシリル)シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(プロパン-2-イル)ピリダジン-3-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(プロパン-2-イル)ピラジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[5-(プロパン-2-イル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[5-(プロパン-2-イル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[4-(プロパン-2-イル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{(1R,3R)-2,2-ジフルオロ-3-[4-(3-フルオロフェニル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[2-(ジメチルアミノ)ピリミジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[2-(シクロペンチルアミノ)ピリミジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[2-(ベンジルアミノ)ピリミジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
tert-ブチル4-{4-[トランス-2-(4-スルファモイルフェニル)シクロプロピル]ピリミジン-2-イル}ピペラジン-1-カルボキシレート;
4-(トランス-2-{2-[(2,2-ジメチルプロピル)アミノ]ピリミジン-4-イル}シクロプロピル)ベンゼンスルホンアミド;
4-(トランス-2-{2-[メチル(フェニル)アミノ]ピリミジン-4-イル}シクロプロピル)ベンゼンスルホンアミド;
4-{トランス-2-[2-(ピロリジン-1-イル)ピリミジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
4-(トランス-2-{2-[(4-フルオロフェニル)アミノ]ピリミジン-4-イル}シクロプロピル)ベンゼンスルホンアミド;
4-[トランス-2-(2-フェニルピリミジン-4-イル)シクロプロピル]ベンゼンスルホンアミド;
4-(トランス-2-{2-[(2-フェニルエチル)アミノ]ピリミジン-4-イル}シクロプロピル)ベンゼンスルホンアミド;
4-{トランス-2-[2-(フェニルアミノ)ピリミジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[2-(プロパン-2-イル)ピリジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[2-(プロパン-2-イル)ピリジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
4-[トランス-2-(2-シクロブチルピリジン-4-イル)シクロプロピル]ベンゼンスルホンアミド;
4-{トランス-2-[4-(1H-イミダゾール-1-イル)フェニル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[3-(1H-1,2,4-トリアゾール-1-イル)フェニル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(プロパン-2-イル)ピリジン-3-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[5-(ピロリジン-1-イル)ピリジン-3-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(1H-ピラゾール-1-イル)ピリジン-3-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(プロパン-2-イルオキシ)ピリジン-3-イル]シクロプロピル}ベンゼンスルホンアミド;及び
4-{トランス-2-[6-(2-シアノプロパン-2-イル)ピリジン-3-イル]シクロプロピル}ベンゼンスルホンアミド
から選択される化合物又は薬学的に許容されるその塩に関するものでもある。
The present invention also comprises the following exemplary compounds:
4- {Trans-2- [6- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [2- (morpholine-4-yl) pyrimidin-4-yl] cyclopropyl} benzenesulfonamide;
4- [Trans-2- (6-cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide;
4- [Trans-2- (5-cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide;
4- {Trans-2- [4- (Propane-2-yl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (pyrrolidin-1-yl) pyridin-3-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [3- (5-methyl-1,2,4-oxadiazole-3-yl) phenyl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [2- (Propane-2-yl) Pyridine-4-yl] cyclopropyl} benzenesulfonamide;
4-[(1R, 3R) -2,2-dimethyl-3-{4- [5- (trifluoromethyl) pyridin-3-yl] pyrimidine-2-yl} cyclopropyl] benzenesulfonamide;
4- {Trans-2- [4- (3-fluorophenyl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide;
4- (Trans-2- {4- [5- (trifluoromethyl) pyridin-3-yl] pyrimidin-2-yl} cyclopropyl) benzenesulfonamide;
4- {Trans-2- [6- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [4- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [5- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- [Trans-2- (6-cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide;
4- {Trans-2- [5- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [5- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [3- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (1H-pyrazole-1-yl) pyridin-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (tetrahydro-2-H-pyran-4-yl) pyridin-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [4- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- [Trans-2- (6-cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide;
4- [Trans-2- (5-cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide;
4- {2- [6- (Propane-2-yl) Pyridine-3-yl] -3- (trimethylsilyl) cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (Propane-2-yl) pyridazine-3-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (Propane-2-yl) pyrazine-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [5- (Propane-2-yl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [5- (Propane-2-yl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [4- (Propane-2-yl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide;
4-{(1R, 3R) -2,2-difluoro-3- [4- (3-fluorophenyl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [2- (dimethylamino) pyrimidin-4-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [2- (cyclopentylamino) pyrimidin-4-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [2- (benzylamino) pyrimidin-4-yl] cyclopropyl} benzenesulfonamide;
tert-Butyl 4- {4- [trans-2- (4-sulfamoylphenyl) cyclopropyl] pyrimidine-2-yl} piperazine-1-carboxylate;
4- (Trans-2-{2-[(2,2-dimethylpropyl) amino] pyrimidin-4-yl} cyclopropyl) benzenesulfonamide;
4- (Trans-2- {2- [methyl (phenyl) amino] pyrimidin-4-yl} cyclopropyl) benzenesulfonamide;
4- {Trans-2- [2- (pyrrolidin-1-yl) pyrimidin-4-yl] cyclopropyl} benzenesulfonamide;
4- (Trans-2-{2-[(4-fluorophenyl) amino] pyrimidin-4-yl} cyclopropyl) benzenesulfonamide;
4- [Trans-2- (2-phenylpyrimidine-4-yl) cyclopropyl] benzenesulfonamide;
4- (Trans-2-{2-[(2-phenylethyl) amino] pyrimidin-4-yl} cyclopropyl) benzenesulfonamide;
4- {Trans-2- [2- (Phenylamino) pyrimidin-4-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [2- (Propane-2-yl) Pyridine-4-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [2- (Propane-2-yl) Pyridine-4-yl] cyclopropyl} benzenesulfonamide;
4- [Trans-2- (2-Cyclobutylpyridin-4-yl) cyclopropyl] benzenesulfonamide;
4- {Trans-2- [4- (1H-imidazol-1-yl) phenyl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [3- (1H-1,2,4-triazole-1-yl) phenyl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (Propane-2-yl) pyridine-3-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [5- (pyrrolidin-1-yl) pyridin-3-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (1H-pyrazole-1-yl) pyridin-3-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (Propyl-2-yloxy) Pyridine-3-yl] cyclopropyl} benzenesulfonamide; and 4- {Trans-2- [6- (2-Cyanopropane-2-yl] It also relates to a compound selected from pyridine-3-yl] cyclopropyl} benzenesulfonamide or a pharmaceutically acceptable salt thereof.
本発明の他の実施形態は、次のものを含む。 Other embodiments of the invention include:
(a)式Iの化合物及び薬学的に許容される担体を含む医薬組成物。 (A) A pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier.
(b)アセチルコリンエステラーゼ阻害剤、例えばドネペジル、リバスティグミン及びガランタミン;NMDA受容体拮抗薬、例えばメマンチン;β-セクレターゼ阻害剤、例えばベルベセスタット及びAZD3293;M4mAChR作動薬又はPAM;mGluR2拮抗薬又はNAM又はPAM;5-HT6拮抗薬、例えばイダロピルジン、RVT-101、AVN-101、AVN322、SUVN-502及びSYN-120;ヒスタミンH3受容体拮抗薬、例えばS38093;PDE4阻害剤、例えばHT0712;PDE9阻害剤、例えばBI40936;HDAC6阻害剤;抗精神病薬;LRRK2阻害剤;MAO-B阻害剤;及びレボドパからなる群から選択される第2の治療剤をさらに含む(a)の医薬組成物。 (B) Acetylcholinesterase inhibitors such as donepezil, rivastigmin and galantamine; NMDA receptor antagonists such as memantine; β-secretase inhibitors such as velvecestat and AZD3293; M4mAChR agonist or PAM; mGluR2 antagonist or NAM. Or PAM; 5-HT6 antagonists such as idalopyrdin, RVT-101, AVN-101, AVN322, SUVN-502 and SYN-120; histamine H3 receptor antagonists such as S38093; PDE4 inhibitors such as HT0712; PDE9 inhibitors. The pharmaceutical composition of (a) further comprising, for example, a BI40936; HDAC6 inhibitor; an antipsychotic agent; an LRRK2 inhibitor; a MAO-B inhibitor; and a second therapeutic agent selected from the group consisting of levodopa.
(c)前記第2の治療剤が、クロザピン、オランザピン、リスペリドン、アリピプラゾール、クエチアピン、ハロペリドール、ロキサピン、チオリダジン、モリンドン、チオチキセン、フルフェナジン、メソリダジン、トリフルオペラジン、クロルプロマジン及びペルフェナジンからなる群から選択される抗精神病薬である、(b)の医薬組成物。 (C) The second therapeutic agent is selected from the group consisting of clozapine, olanzapine, risperidone, alipiprazole, quetiapine, haloperidol, loxapine, thioridazine, morindon, thiothixene, fluphenazine, mesoridazine, trifluoperazine, chlorpromazine and perphenazine. The pharmaceutical composition of (b), which is an antipsychotic drug.
(d)(i)式Iの化合物、及び、(ii)アセチルコリンエステラーゼ阻害剤、例えばドネペジル、リバスティグミン及びガランタミン;NMDA受容体拮抗薬、例えばメマンチン;β-セクレターゼ阻害剤、例えばベルベセスタット及びAZD3293;M4mAChR作動薬又はPAM;mGluR2拮抗薬又はNAM又はPAM;5-HT6拮抗薬、例えばイダロピルジン、RVT-101、AVN-101、AVN322、SUVN-502及びSYN-120;ヒスタミンH3受容体拮抗薬、例えばS38093;PDE4阻害剤、例えばHT0712;PDE9阻害剤、例えばBI40936;HDAC6阻害剤;抗精神病薬;LRRK2阻害剤;MAO-B阻害剤;及びレボドパからなる群から選択される第2の治療剤、である医薬組み合わせであって、ここで、式Iの化合物及び第2の治療剤がそれぞれアルツハイマー病、パーキンソン病及び統合失調症に関連する認知機能障害を治療する上で有効な組み合わせとする量で用いられる、医薬組み合わせ。 (D) Compounds of formula I and (ii) acetylcholinesterase inhibitors such as donepezil, rivastigmin and galantamine; NMDA receptor antagonists such as memantine; β-secretase inhibitors such as velvecestat and AZD3293; M4mAChR agonist or PAM; mGluR2 antagonist or NAM or PAM; 5-HT6 antagonists such as idalopyrdin, RVT-101, AVN-101, AVN322, SUVN-502 and SYN-120; histamine H3 receptor antagonists, A second therapeutic agent selected from the group consisting of, for example, S38093; PDE4 inhibitor, eg HT0712; PDE9 inhibitor, eg BI40936; HDAC6 inhibitor; antipsychotic drug; LRRK2 inhibitor; MAO-B inhibitor; Is a pharmaceutical combination, wherein the compound of formula I and the second therapeutic agent are in an effective combination for treating cognitive dysfunction associated with Alzheimer's disease, Parkinson's disease and schizophrenia, respectively. A pharmaceutical combination used.
(e)前記第2の治療剤が、クロザピン、オランザピン、リスペリドン、アリピプラゾール、クエチアピン、ハロペリドール、ロキサピン、チオリダジン、モリンドン、チオチキセン、フルフェナジン、メソリダジン、トリフルオペラジン、クロルプロマジン及びペルフェナジンからなる群から選択される抗精神病薬である、(d)の組み合わせ。 (E) The second therapeutic agent is selected from the group consisting of clozapine, olanzapine, risperidone, alipiprazole, quetiapine, haloperidol, loxapine, thioridazine, morindon, thiothixene, fluphenazine, mesoridazine, trifluoperazine, chlorpromazine and perphenazine. The combination of (d), which is an antipsychotic drug.
(f)処置を必要とする対象者におけるα7nAChR活性を調節するための医薬の製造における式Iの化合物の使用。 (F) Use of a compound of formula I in the manufacture of a pharmaceutical to regulate α7nAChR activity in a subject in need of treatment.
(g)処置を必要とする対象者でのアルツハイマー病、パーキンソン病及び統合失調症に関連する認知機能障害を治療するための医薬の製造における式Iの化合物の使用。 (G) Use of a compound of formula I in the manufacture of a pharmaceutical for treating cognitive dysfunction associated with Alzheimer's disease, Parkinson's disease and schizophrenia in subjects in need of treatment.
(h)アルツハイマー病、パーキンソン病及び統合失調症に関連する認知機能障害を治療する、及び/又は処置を必要とする対象者でのアルツハイマー病、パーキンソン病及び統合失調症に関連する認知機能障害の徴候の可能性若しくは重度を低下させる方法であって、有効量の式Iの化合物を当該対象者に投与することを含む方法。 (H) Of Alzheimer's disease, Parkinson's disease and schizophrenia-related cognitive dysfunction in subjects who treat and / or require treatment for cognitive dysfunction associated with Alzheimer's disease, Parkinson's disease and schizophrenia. A method of reducing the likelihood or severity of a sign, comprising administering to the subject an effective amount of a compound of formula I.
(i)式Iの化合物を、有効量のアセチルコリンエステラーゼ阻害剤、例えばドネペジル、リバスティグミン及びガランタミン;NMDA受容体拮抗薬、例えばメマンチン;β-セクレターゼ阻害剤、例えばベルベセスタット及びAZD3293;M4mAChR作動薬又はPAM;mGluR2拮抗薬又はNAM又はPAM;5-HT6拮抗薬、例えばイダロピルジン、RVT-101、AVN-101、AVN322、SUVN-502及びSYN-120;ヒスタミンH3受容体拮抗薬、例えばS38093;PDE4阻害剤、例えばHT0712;PDE9阻害剤、例えばBI40936;HDAC6阻害剤;抗精神病薬;LRRK2阻害剤;MAO-B阻害剤;及びレボドパからなる群から選択される少なくとも一つの第2の治療剤と組み合わせて投与する、(h)の方法。 (I) The compound of formula I is subjected to effective amounts of acetylcholinesterase inhibitors such as donepezil, rivastigmin and galantamine; NMDA receptor antagonists such as memantine; β-secretase inhibitors such as velvecestat and AZD3293; M4mAChR activation. Drugs or PAMs; mGluR2 antagonists or NAMs or PAMs; 5-HT6 antagonists such as idalopyrdin, RVT-101, AVN-101, AVN322, SUVN-502 and SYN-120; histamine H3 receptor antagonists such as S38093; PDE4 Combined with at least one second therapeutic agent selected from the group consisting of inhibitors such as HT0712; PDE9 inhibitors such as BI40936; HDAC6 inhibitors; antipsychotics; LRRK2 inhibitors; MAO-B inhibitors; (H).
(j)前記第2の治療剤が、クロザピン、オランザピン、リスペリドン、アリピプラゾール、クエチアピン、ハロペリドール、ロキサピン、チオリダジン、モリンドン、チオチキセン、フルフェナジン、メソリダジン、トリフルオペラジン、クロルプロマジン及びペルフェナジンからなる群から選択される抗精神病薬である、(i)の方法。 (J) The second therapeutic agent is selected from the group consisting of clozapine, olanzapine, risperidone, alipiprazole, quetiapine, haloperidol, loxapine, thioridazine, morindon, thiothixene, fluphenazine, mesoridazine, trifluoperazine, chlorpromazine and perphenazine. The method (i), which is an antipsychotic drug.
(k)処置を必要とする対象者でのα7nAChR活性の調節方法であって、当該対象者に対して、(a)、(b)若しくは(c)の医薬組成物、又は、(d)若しくは(e)の組み合わせを投与することを含む方法。 (K) A method for regulating α7nAChR activity in a subject in need of treatment, wherein the pharmaceutical composition of (a), (b) or (c), or (d) or A method comprising administering the combination of (e).
(l)アルツハイマー病、パーキンソン病及び統合失調症に関連する認知機能障害を治療し、及び/又は処置を必要とする対象者でのアルツハイマー病、パーキンソン病及び統合失調症に関連する認知機能障害の徴候の可能性若しくは重度を低下させる方法であって、当該対象者に対して、(a)、(b)若しくは(c)の医薬組成物、又は、(d)若しくは(e)の組み合わせを投与することを含む方法。 (L) Of Alzheimer's disease, Parkinson's disease and schizophrenia-related cognitive dysfunction in subjects in need of treatment and / or treatment for cognitive dysfunction associated with Alzheimer's disease, Parkinson's disease and schizophrenia. A method for reducing the possibility or severity of symptoms, wherein the subject is administered with the pharmaceutical composition of (a), (b) or (c), or a combination of (d) or (e). Methods that include doing.
上記で提供の化合物及び塩の実施形態において、理解すべき点として、各実施形態は、そのような組み合わせが安定な化合物若しくは塩を提供し、実施形態の説明と一致するような程度に、1以上の他の実施形態と組み合わせることができる。さらに理解すべき点として、上記の(a)~(l)として提供された組成物及び方法の実施形態が、実施形態の組み合わせからの結果としてのそのような実施形態を含む化合物及び/又は塩の全ての実施形態を含むものと理解される。 In embodiments of the compounds and salts provided above, it should be understood that each embodiment provides a stable compound or salt in such a combination to the extent that it is consistent with the description of the embodiment. It can be combined with the above other embodiments. It should be further understood that the embodiments of the compositions and methods provided as (a)-(l) above include compounds and / or salts comprising such embodiments as a result of a combination of embodiments. It is understood to include all embodiments of.
本発明の追加の実施形態は、上記(a)~(l)に記載の医薬組成物、組み合わせ、使用及び方法であって、そこで使用される本発明の化合物が上記の化合物の実施形態、態様、分類、下位分類若しくは特徴的なもののうちの一つの化合物であるものを含む。これらの実施形態の全てにおいて、当該化合物は、場合により薬学的に許容される塩若しくは水和物の形態で用いられても良い。 An additional embodiment of the present invention is the pharmaceutical composition, combination, use and method according to the above (a) to (l), wherein the compound of the present invention used therein is an embodiment or embodiment of the above compound. , Classification, subclassification or one of the characteristic compounds. In all of these embodiments, the compound may be used in the form of optionally pharmaceutically acceptable salts or hydrates.
本発明はまた、(a)アルツハイマー病、パーキンソン病、統合失調症及びL-DOPA誘発運動障害に関連する認知機能障害を予防若しくは治療するための、又は(b)アルツハイマー病、パーキンソン病、統合失調症及びL-DOPA誘発運動障害に関連する認知機能障害を治療するための、及び/又はアルツハイマー病、パーキンソン病、統合失調症及びL-DOPA誘発運動障害に関連する認知機能障害の可能性若しくは徴候の重度を低下させるための、又は(c)医療分野で使用するための、(i)そのための、(ii)医薬としての、又は(iii)医薬製造での使用のための、本発明の化合物を含む。これらの使用において、本発明の化合物は、アセチルコリンエステラーゼ阻害剤、例えばドネペジル、リバスティグミン及びガランタミン;NMDA受容体拮抗薬、例えばメマンチン;β-セクレターゼ阻害剤、例えばベルベセスタット及びAZD3293;M4mAChR作動薬又はPAM;mGluR2拮抗薬又はNAM又はPAM;5-HT6拮抗薬、例えばイダロピルジン、RVT-101、AVN-101、AVN322、SUVN-502及びSYN-120;ヒスタミンH3受容体拮抗薬、例えばS38093;PDE4阻害剤、例えばHT0712;PDE9阻害剤、例えばBI40936;HDAC6阻害剤;抗精神病薬;LRRK2阻害剤;MAO-B阻害剤;及びレボドパから選択される1以上の第2の治療剤と組み合わせて使用しても良い。 The invention also relates to (a) Alzheimer's disease, Parkinson's disease, schizophrenia and cognitive dysfunction associated with L-DOPA-induced movement disorders, or (b) Alzheimer's disease, Parkinson's disease, schizophrenia. Potential or signs of cognitive dysfunction associated with disease and L-DOPA-induced dyskinesia and / or Alzheimer's disease, Parkinson's disease, schizophrenia and L-DOPA-induced dyskinesia. The compounds of the invention for reducing the severity of, or (c) for use in the medical field, (i) for that purpose, (ii) as a drug, or (iii) for use in pharmaceutical production. including. In these uses, the compounds of the invention are acetylcholinesterase inhibitors such as donepezil, rivastigmin and galantamine; NMDA receptor antagonists such as memantin; β-secretase inhibitors such as velvecestat and AZD3293; M4mAChR agonists. Or PAM; mGluR2 antagonist or NAM or PAM; 5-HT6 antagonist, such as idalopyrdin, RVT-101, AVN-101, AVN322, SUVN-502 and SYN-120; histamine H3 receptor antagonist, eg S38093; PDE4 inhibition. Agents such as HT0712; PDE9 inhibitors such as BI40936; HDAC6 inhibitors; antipsychotics; LRRK2 inhibitors; MAO-B inhibitors; and used in combination with one or more second therapeutic agents selected from levodopa. Is also good.
化学名、一般名及び化学構造は、同じ構造を説明するのに互換的に用いることができる。 Chemical names, common names and chemical structures can be used interchangeably to describe the same structure.
本明細書で使用される場合、「6員アリール又はヘテロアリール環」という用語は、O、N及びSからなる群から選択される0~4個のヘテロ原子を含む安定な不飽和6員環を指す。この定義の範囲に含まれる6員アリール又はヘテロアリール環には、ピリジン、ピリミジン、フェニル、ピリダジン及びピラジンを含み、これらに限定されるものではない。 As used herein, the term "6-membered aryl or heteroaryl ring" is a stable unsaturated 6-membered ring containing 0-4 heteroatoms selected from the group consisting of O, N and S. Point to. 6-membered aryl or heteroaryl rings within the scope of this definition include, but are not limited to, pyridine, pyrimidine, phenyl, pyridazine and pyrazine.
本明細書で使用される場合、本発明の化合物に関連しての「投与」という用語及びそれの変形形態(例えば、化合物を「投与すること」)は、処置を必要とする個体に対して当該化合物を提供することを意味する。本発明の化合物が1種以上の他の活性薬剤(例えば、コリンエステラーゼ阻害剤、例えばドネペジル、リバスティグミン及びガランタミン)と組み合わせて提供されるとき、「投与」及びその変形形態はそれぞれ、当該化合物もしくはそれの塩と他の作用剤を同時に又は順次に提供することを含むものと理解される。 As used herein, the term "administration" in connection with a compound of the invention and variants thereof (eg, "administering" a compound) are used to an individual in need of treatment. It means to provide the compound. When the compounds of the invention are provided in combination with one or more other active agents (eg, cholinesterase inhibitors such as donepezil, ribastigmin and galantamine), the "administration" and variants thereof are the compounds or variants thereof, respectively. It is understood to include providing a salt thereof and other agents simultaneously or sequentially.
「アルコキシ」という用語は、「アルキル-O」基を指す。アルコキシ基は、指示されたように置換されていても良い。 The term "alkoxy" refers to an "alkyl-O" group. Alkoxy groups may be substituted as indicated.
「アルキル」という用語は、水素原子のうちの一つが結合で置き換わっている脂肪族炭化水素基を指す。アルキル基は、直鎖若しくは分岐であることができ、1~12個の炭素原子を含むことができる。異なる実施形態において、アルキル基は1~6個の炭素原子[(C1-C6)アルキル]又は1~4個の炭素原子[(C1-C4)アルキル]又は1~3個の炭素原子[(C1-C3)アルキル]を含む。アルキル基の例には、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、sec-ブチル、イソブチル、tert-ブチル、n-ペンチル、ネオペンチル、イソペンチル、n-ヘキシル、イソヘキシル及びネオヘキシルを含み、これらに限定されるものではない。1実施形態において、アルキル基は直鎖である。別の実施形態において、アルキル基は分岐である。 The term "alkyl" refers to an aliphatic hydrocarbon group in which one of the hydrogen atoms is replaced by a bond. Alkyl groups can be linear or branched and can contain 1-12 carbon atoms. In different embodiments, the alkyl group is 1 to 6 carbon atoms [(C 1 -C 6 ) alkyl] or 1 to 4 carbon atoms [(C 1 to C 4 ) alkyl] or 1 to 3 carbons. Contains the atom [ ( C1 - C3) alkyl]. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. Not limited to. In one embodiment, the alkyl group is linear. In another embodiment, the alkyl group is branched.
「アルキニル」という用語は、2~12個の炭素原子及び少なくとも1個の炭素-炭素三重結合を含む直鎖若しくは分岐の炭化水素基を指す。3個までの炭素-炭素三重結合が存在していても良い。従って、「C2-C6アルキニル」は、2~6個の炭素原子を有するアルキニル基を意味する。アルキニル基には、エチニル、プロピニル、ブチニル、3-メチルブチニルを含む。1実施形態において、アルキニル基は直鎖である。別の実施形態において、アルキニル基は分岐である。 The term "alkynyl" refers to a linear or branched hydrocarbon group containing 2-12 carbon atoms and at least one carbon-carbon triple bond. Up to 3 carbon-carbon triple bonds may be present. Therefore, "C2 - C6 alkynyl" means an alkynyl group having 2 to 6 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl, 3-methylbutynyl. In one embodiment, the alkynyl group is linear. In another embodiment, the alkynyl group is branched.
「アリール」(又は「アリール環系」)という用語は、単環式及び多環式炭素環系を指し、ここで、多環系における個々の炭素環は縮合しているか単結合を介して互いに結合しており、そしてここで、少なくとも1個の環は芳香環である。好適なアリール基には、フェニル、インダニル、ナフチル、テトラヒドロナフチル、及びビフェニルを含む。アリール環系には、適切な場合、特定の環原子が結合している可変要素の指示が含まれていても良い。別段の断りがない限り、アリール環系に対する置換基は、いずれの環原子に結合していても良いが、但し、そのような結合は安定な環系の形成に至るものである。 The term "aryl" (or "aryl ring system") refers to monocyclic and polycyclic carbocycles, where the individual carbocycles in the polycyclic system are fused or mutually via a single bond. Bonded, and here at least one ring is an aromatic ring. Suitable aryl groups include phenyl, indanyl, naphthyl, tetrahydronaphthyl, and biphenyl. Aryl ring systems may include, where appropriate, indications of variable elements to which a particular ring atom is attached. Unless otherwise specified, the substituents on the aryl ring system may be attached to any ring atom, provided that such a bond leads to the formation of a stable ring system.
「組成物」という用語は、特定の成分を含む産物、ならびに特定の成分を組み合わせることで得られる産物を包含することを意図する。 The term "composition" is intended to include products containing specific ingredients, as well as products obtained by combining specific ingredients.
「化合物」という用語は、全ての形態での一般式Iによって記載された化学薬剤を包含することを意図する。そのような化学薬剤は、水和物、溶媒和物及び多形体のような異なる形態で存在していることができる。 The term "compound" is intended to include the chemical agents described by General Formula I in all forms. Such chemical agents can be present in different forms such as hydrates, solvates and polymorphs.
本明細書で使用される「シクロアルキル」という用語は、3~10個の環炭素原子を含む非芳香族単環式又は多環式環系を指す。1実施形態において、シクロアルキルは、5~10個の環炭素原子を含む。別の実施形態において、シクロアルキルは、3~7個の環原子を含む。別の実施形態において、シクロアルキルは、3~6個の環原子を含む[(C3-C6)シクロアルキル]。別の実施形態において、シクロアルキルは、5~7個の環原子を含む。別の実施形態において、シクロアルキルは、5~6個の環原子を含む。「シクロアルキル」という用語は、アリール(例えば、ベンゼン)又はヘテロアリール環に縮合している上記で定義のシクロアルキル基も含む。単環式シクロアルキルの例には、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル及びシクロオクチルを含み、これらに限定されるものではない。多環式シクロアルキルの例には、1-デカリニル、ノルボニル、ビシクロ[3.1.0]ヘキシル及びアダマンチルを含み、これらに限定されるものではない。「3~7員シクロアルキル」という用語は、3~7個の環炭素原子を有するシクロアルキル基を指す。シクロアルキル基の環炭素原子は、カルボニル基として官能化されていても良い。そのようなシクロアルキル基(本明細書においては、「シクロアルカノイル」基とも称される)の例示的な例には、シクロブタノイルを含み、それに限定されるものではない。
本明細書で使用される「有効量」という用語は、研究者、獣医、医師又は臨床関係者が探求している組織、系、動物若しくはヒトでの生理的応答若しくは医学的応答を誘発する活性化合物又は医薬剤の量を意味する。1実施形態において、有効量は、処置される疾患若しくは症状の1以上の徴候の改善のための「治療上有効量」である。別の実施形態において、有効量は、疾患若しくは症状の1以上の徴候の重度若しくは可能性を低下させるための「予防上有効量」である。その用語は、本明細書において、α7nAChR活性を調節し、それにより追求されている応答を誘発するのに十分な活性化合物の量も含む(即ち、「治療上有効量」)。活性化合物(即ち、有効成分)を塩として投与する場合、有効成分についての言及は、その化合物の遊離酸若しくは遊離塩基形態についてのものである。 As used herein, the term "effective amount" is an activity that elicits a physiological or medical response in a tissue, system, animal or human that is being sought by researchers, veterinarians, physicians or clinical personnel. Means the amount of compound or pharmaceutical agent. In one embodiment, the effective amount is a "therapeutically effective amount" for ameliorating one or more signs of the disease or symptom being treated. In another embodiment, the effective amount is a "preventive effective amount" for reducing the severity or likelihood of one or more signs of the disease or symptom. The term also includes, herein, an amount of active compound sufficient to regulate α7nAChR activity and thereby elicit the response pursued (ie, "therapeutically effective amount"). When the active compound (ie, the active ingredient) is administered as a salt, the reference to the active ingredient refers to the free acid or free base form of the compound.
「ハロゲン」(又は「ハロ」)という用語は、フッ素、塩素、臭素及びヨウ素(別の呼称では、フルオロ、クロロ、ブロモ及びヨードと称される。)の原子を指す。 The term "halogen" (or "halo") refers to the atoms of fluorine, chlorine, bromine and iodine (otherly referred to as fluoro, chloro, bromo and iodine).
本明細書で使用される「ヘテロアリール」という用語は、5~14環原子を含む単環式若しくは多環式環系であって、ここで、環原子のうちの1~4個が独立にO、N若しくはSであり、そしてここで、残りの環原子が炭素原子であり、少なくとも1個の環が芳香族であるものを指す。1実施形態において、ヘテロアリール基は、5~10個の環原子を有する。別の実施形態において、ヘテロアリール基は単環式であり、5個若しくは6個の環原子を有する。別の実施形態において、ヘテロアリール基は二環式であり、9個若しくは10個の環原子を有する。ヘテロアリール基は通常、環炭素原子を介して結合しているが、非炭素原子を介して結合していても良く、但し、それによって安定な化合物となるものであり、そして、ヘテロアリールのいずれの窒素原子も酸化されて相当するN-オキサイドとなっていても良い。「ヘテロアリール」という用語は、ベンゼン環に縮合している上記で定義のヘテロアリール基も包含する。「ヘテロアリール」という用語は、少なくとも1個のN、O及びSから選択される環ヘテロ原子を含む縮合多環式環系であって、ここで、その縮合多環式環系のうちの少なくとも1個の環が芳香族であるものも包含する。例えば、「9~10員の二環式ヘテロアリール」という用語は、ベンゼン環若しくはピリジル環に縮合している非芳香族5員複素環を包含する。ヘテロアリールの例には、ベンゾイミダゾリル、ベンゾイミダゾロニル、ベンゾフラニル、ベンゾフラザニル、ベンゾピラゾリル、ベンゾトリアゾリル、ベンゾチオフェニル、ベンゾオキサゾリル、カルバゾリル、カルボリニル、シンノリニル、フラニル、イミダゾリル、インドリニル、インドリル、インドラジニル、インダゾリル、イソベンゾフラニル、イソインドリル、イソキノリル、イソチアゾリル、イソオキサゾリル、ナフトピリジニル、オキサジアゾリル、オキサゾリル、ピラジニル、ピラゾリル、ピリダジニル、ピリドピリジニル、ピリダジニル、ピリジル、ピリミジル、ピロリル、キナゾリニル、キノリル、キノキサリニル、テトラゾリル、テトラゾロピリジル、チアジアゾリル、チアゾリル、チエニル、トリアゾリル、ジヒドロベンゾイミダゾリル、ジヒドロベンゾフラニル、ジヒドロベンゾチオフェニル、ジヒドロベンゾオキサゾリル、ジヒドロインドリル、ジヒドロキノリニル、メチレンジオキシベンゾリルなど及びこれらの全ての異性体型を含み、これらに限定されるものではない。「ヘテロアリール」という用語は、例えばテトラヒドロイソキノリル、テトラヒドロキノリルのような部分飽和ヘテロアリール部分も指し、但し、それらは少なくとも1個の芳香環を含む。1実施形態において、ヘテロアリール基は5員ヘテロアリールである。別の実施形態において、ヘテロアリール基は6員ヘテロアリールである。別の実施形態において、ヘテロアリール基は、ベンゼン環に縮合した5~6員ヘテロアリール基を含む。 As used herein, the term "heteroaryl" is a monocyclic or polycyclic ring system containing 5 to 14 ring atoms, wherein 1 to 4 of the ring atoms are independent. O, N or S, where the remaining ring atoms are carbon atoms and at least one ring is aromatic. In one embodiment, the heteroaryl group has 5-10 ring atoms. In another embodiment, the heteroaryl group is monocyclic and has 5 or 6 ring atoms. In another embodiment, the heteroaryl group is bicyclic and has 9 or 10 ring atoms. Heteroaryl groups are usually attached via a ring carbon atom, but may be attached via a non-carbon atom, provided that they are stable compounds and are either heteroaryl. The nitrogen atom of the above may also be oxidized to the corresponding N-oxide. The term "heteroaryl" also includes the heteroaryl group as defined above that is condensed on the benzene ring. The term "heteroaryl" is a fused polycyclic ring system comprising at least one ring heteroatom selected from N, O and S, wherein at least one of the fused polycyclic ring systems thereof. It also includes those in which one ring is aromatic. For example, the term "9-10 membered bicyclic heteroaryl" includes a non-aromatic 5-membered heterocyclic ring fused to a benzene ring or a pyridyl ring. Examples of heteroaryls include benzoimidazolyl, benzoimidazolonyl, benzofuranyl, benzofrazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indrazinyl. , Indazolyl, Isobenzofuranyl, Isoindrill, Isoquinolyl, Isothiazolyl, Isooxazolyl, Naftpyridinyl, Oxaziazolyl, Oxazolyl, Pyrazineyl, Pyrazolyl, Pyridazinyl, Pyridopyridinyl, Pyridadinyl, Pyridyl, Pyrimidyl, Pyrrolyl, Kinazolinyl, Kinolyl, Kinoxalinyl, Tetrazolyl Thiasiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindrill, dihydroquinolinyl, methylenedioxybenzolyl, etc. and all their isomers Including, but not limited to. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as tetrahydroisoquinolyl, tetrahydroquinolyl, but they include at least one aromatic ring. In one embodiment, the heteroaryl group is a 5-membered heteroaryl. In another embodiment, the heteroaryl group is a 6-membered heteroaryl. In another embodiment, the heteroaryl group comprises a 5- to 6-membered heteroaryl group condensed into a benzene ring.
本明細書で使用される「複素環」又は「複素環式」という用語は、O、N及びSからなる群から選択される1~4個のヘテロ原子を含む3~10員の非芳香族複素環を意味するものであり、そして、単環式若しくは二環式の基(縮合、架橋又はスピロ環状)を含む。「複素環」のさらなる例には、オキサゾリン、イソオキサゾリン、オキセタニル、テトラヒドロピラニル、アゼチジニル、1,4-ジオキサニル、ヘキサヒドロアゼピニル、ピペラジニル、ピペリジニル、ピロリジニル、モルホリニル、チオモルホリニル、ジヒドロフラニル、ジヒドロイミダゾリル、ジヒドロイソオキサゾリル、ジヒドロイソチアゾリル、ジヒドロオキサジアゾリル、ジヒドロオキサゾリル、ジヒドロピラジニル、ジヒドロピラゾリル、ジヒドロピリジニル、ジヒドロピリミジニル、ジヒドロピロリル、ジヒドロテトラゾリル、ジヒドロチアジアゾリル、ジヒドロチアゾリル、ジヒドロチエニル、ジヒドロトリアゾリル、テトラヒドロフラニル及びテトラヒドロチエニル、並びにそれらのN-オキサイドを含むが、これらに限定されるものではない。複素環置換基の結合は、炭素原子又はヘテロ原子を介して行われ得る。 As used herein, the term "heterocycle" or "heterocyclic" is a 3-10 member non-aromatic containing 1 to 4 heteroatoms selected from the group consisting of O, N and S. It means a heterocycle and includes monocyclic or bicyclic groups (condensation, cross-linking or spirocyclic). Further examples of "heterocycles" include oxazolines, isoxazolines, oxetanyl, tetrahydropyranyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, dihydro. Imidazolyl, dihydroisoxazoline, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazoline, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydrotetrazolyl, dihydrothia Includes, but is not limited to, diazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, tetrahydrofuranyl and tetrahydrothienyl, and their N-oxides. Bonding of heterocyclic substituents can be carried out via a carbon atom or a heteroatom.
本明細書で使用される「ヒドロキシアルキル」という用語は、アルキル基の水素原子のうちの1以上が-OH基によって置き換わっている、上記で定義のアルキル基を指す。1実施形態において、ヒドロキシアルキル基は、1~6個の炭素原子を有する。ヒドロキシアルキル基の例には、-CH2OH、-CH2CH2OH、-CH2CH2CH2OH及び-CH2CH(OH)CH3を含むが、これらに限定されるものではない。「C1-C6ヒドロキシアルキル」という用語は、1~6個の炭素原子を有するヒドロキシアルキル基を指す。「C1-C4ヒドロキシアルキル」という用語は、1~4個の炭素原子を有するヒドロキシアルキル基を指す。「C1-C3ヒドロキシアルキル」という用語は、1~3個の炭素原子を有するヒドロキシアルキル基を指す。 As used herein, the term "hydroxyalkyl" refers to an alkyl group as defined above, in which one or more of the hydrogen atoms of the alkyl group is replaced by an -OH group. In one embodiment, the hydroxyalkyl group has 1 to 6 carbon atoms. Examples of hydroxyalkyl groups include, but are not limited to, -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH and -CH 2 CH (OH) CH 3 . .. The term "C1 - C 6 hydroxyalkyl" refers to a hydroxyalkyl group having 1 to 6 carbon atoms. The term "C1- C4 hydroxyalkyl" refers to a hydroxyalkyl group having 1 to 4 carbon atoms. The term "C 1 -C 3 hydroxyalkyl" refers to a hydroxyalkyl group having 1 to 3 carbon atoms.
本明細書で使用される場合、「オキソ」又は「=O」という用語は、それが結合している炭素原子とともにカルボニル部分を形成している。 As used herein, the term "oxo" or "= O" forms a carbonyl moiety with the carbon atom to which it is attached.
「薬学的に許容される」は、医薬組成物の成分が互いに適合し、投与を受ける者に対して有害であってはならないことを意味する。 "Pharmaceutically acceptable" means that the components of the pharmaceutical composition are compatible with each other and must not be harmful to the recipient.
アルツハイマー病又は他の神経疾患に関して本明細書で使用される場合の「予防する」という用語は、疾患進行の可能性を低下させることを指す。 As used herein with respect to Alzheimer's disease or other neurological disorders, the term "preventing" refers to reducing the likelihood of disease progression.
本明細書で使用される場合、「対象者」(或いは、「患者」とも称される)という用語は、動物、好ましくは哺乳動物、最も好ましくはヒトを指す。 As used herein, the term "subject" (or also referred to as "patient") refers to an animal, preferably a mammal, most preferably a human.
「置換された」という用語は、指定の原子上の1以上の水素が、その指定の基から選択されたもので置き換わっていることを意味するが、但し、既存の環境下でのその指定された原子の通常の価数を超えるものではなく、そして、その置換によって安定な化合物が生じるものである。逆の意味が明瞭に記載されていない限り、挙げられた置換基による置換基は、そのような置換が化学的に許容され、そして、安定な化合物を与えるのであれば、あらゆる原子上で可能である。置換基及び/又は可変要素の組み合わせは、そのような組み合わせが安定な化合物を与える場合にのみ許容される。「安定な」化合物は、製造及び単離が可能であり、その構造及び特性が本明細書に記載の目的(例えば、対象者への治療的若しくは予防的投与)のための当該化合物の使用を可能とするだけの期間にわたり実質的に未変化のままであるか、実質的に未変化のままとなるようにすることができる化合物である。 The term "replaced" means that one or more hydrogens on a designated atom have been replaced by one selected from the designated group, provided that the designation under existing circumstances. It does not exceed the normal valence of the atom, and its substitution yields a stable compound. Substituents with the listed substituents are possible on any atom as long as such substitutions are chemically acceptable and provide a stable compound, unless the opposite meaning is clearly stated. be. Combinations of substituents and / or variable elements are allowed only if such combinations provide a stable compound. A "stable" compound can be manufactured and isolated, and its structure and properties make use of the compound for the purposes described herein (eg, therapeutic or prophylactic administration to a subject). A compound that can remain substantially unchanged or remain substantially unchanged for as long as possible.
式Iの別の実施形態において、Xは、
から選択され、
R1、R2及びRbはHである。
Selected from
R 1 , R 2 and R b are H.
式Iの別の実施形態において、Xは、
であり、R1及びR2はHである。 And R 1 and R 2 are H.
式Iの別の実施形態において、Yは4個の置換基であり、それらはそれぞれ独立に、H、(C1-C4)アルキル、ハロゲン及びOHから選択され、ここで、前記アルキルは1以上のハロゲン又はOHで置換されていても良い。 In another embodiment of formula I, Y is four substituents, each independently selected from H, (C1- C4 ) alkyl, halogen and OH, where the alkyl is 1 It may be substituted with the above halogen or OH.
式Iの別の実施形態において、YはHである。 In another embodiment of formula I, Y is H.
式Iの別の実施形態において、Aは、6員アリール又はヘテロアリール環であって、それぞれ独立にOH、オキソ、ハロゲン、CN、(C1-C6)アルキル、O(C1-C6)アルキル、NR7R8、(C3-C6)シクロアルキル、アリール、ヘテロアリール及び複素環から選択される1~3個のR基で置換され、ここで、それぞれは、独立にハロゲン、CN、(C1-C4)アルキル、(C=O)O(C1-C4)アルキル及びフェニルから選択される1以上の置換基で置換されていても良い。 In another embodiment of formula I, A is a 6-membered aryl or heteroaryl ring, independently OH, oxo, halogen, CN, (C1-C 6 ) alkyl, O (C 1 - C 6 ). ) Alkyl, NR 7 R 8 , (C 3 -C 6 ) substituted with 1-3 R groups selected from cycloalkyl, aryl, heteroaryl and heterocycles, where each is independently a halogen, It may be substituted with one or more substituents selected from CN, (C 1 -C 4 ) alkyl, (C = O) O (C 1 -C 4 ) alkyl and phenyl.
式Iの別の実施形態において、Aは、6員アリール又はヘテロアリール環であって、それぞれ独立にOH、オキソ、ハロゲン、CN、(C1-C6)アルキル、O(C1-C6)アルキル、NR7R8、(C3-C6)シクロアルキル、アリール、ヘテロアリール及び複素環から選択される1~2個のR基で置換され、ここで、それぞれは、独立にハロゲン、CN、(C1-C4)アルキル、(C=O)O(C1-C4)アルキル及びフェニルから選択される1以上の置換基で置換されていても良い。 In another embodiment of formula I, A is a 6-membered aryl or heteroaryl ring, independently OH, oxo, halogen, CN, (C1-C 6 ) alkyl, O (C 1 - C 6 ). ) Alkyl, NR 7 R 8 , (C 3 -C 6 ) substituted with 1-2 R groups selected from cycloalkyl, aryl, heteroaryl and heterocycles, where each is independently a halogen, It may be substituted with one or more substituents selected from CN, (C 1 -C 4 ) alkyl, (C = O) O (C 1 -C 4 ) alkyl and phenyl.
式Iの別の実施形態において、Aは、ピリジン、ピリミジン、フェニル、ピリダジン、ピラジン、トリアジン、ピリジノン、ピリミジノン、ピラジノン及びピリダジノンから選択され、それぞれ独立に、(C1-C6)アルキル、O(C1-C6)アルキル、NR7R8、(C3-C6)シクロアルキル、アリール、ヘテロアリール及び複素環から選択される1~3個のR基で置換され、ここで、それぞれは、独立にハロゲン、CN、(C1-C4)アルキル、(C=O)O(C1-C4)アルキル及びフェニルから選択される1以上の置換基で置換されていても良い。 In another embodiment of formula I, A is selected from pyridine, pyrimidine, phenyl, pyridazine, pyrazine, triazine, pyridinone, pyrimidinone, pyrazinenone and pyridadinone , respectively, independently (C1 - C6) alkyl, O ( Substituted with 1-3 R groups selected from C1 - C 6 ) alkyl, NR 7 R 8 , (C 3 -C 6 ) cycloalkyl, aryl, heteroaryl and heterocycles, where each is substituted. , Independently substituted with one or more substituents selected from halogen, CN, (C 1 -C 4 ) alkyl, (C = O) O (C 1 -C 4 ) alkyl and phenyl.
式Iの別の実施形態において、Aは、ピリジン、ピリミジン、フェニル、ピリダジン及びピラジンから選択され、それぞれ独立に(C1-C6)アルキル、O(C1-C6)アルキル、NR7R8、(C3-C6)シクロアルキル、アリール、ヘテロアリール及び複素環から選択される1~2個のR基で置換され、ここで、それぞれは、独立にハロゲン、CN、(C1-C4)アルキル、(C=O)O(C1-C4)アルキル及びフェニルから選択される1以上の置換基で置換されていても良い。 In another embodiment of Formula I, A is selected from pyridine, pyrimidine, phenyl, pyridazine and pyrazine, independently (C1 - C6) alkyl, O (C1 - C6 ) alkyl, NR 7 R, respectively . 8 , (C 3 -C 6 ) substituted with 1-2 R groups selected from cycloalkyl, aryl, heteroaryl and heterocycles, where each is independently halogen, CN, (C 1- . It may be substituted with one or more substituents selected from C 4 ) alkyl, (C = O) O (C1 - C 4 ) alkyl and phenyl.
式Iの別の実施形態において、Aは、ピリジン、ピリミジン、フェニル、ピリダジン及びピラジンから選択され、それぞれ独立に、(C1-C6)アルキル、O(C1-C6)アルキル、NR7R8、シクロブチル、シクロペンチル、フェニル、モルホリニル、イミダゾリル、ピラゾリル、オキサジアゾリル、ピロリジニル、トリアゾリル及びテトラヒドロピラニルから選択される1~3個のR基で置換され、ここでそれぞれは、独立にハロゲン、CN、(C1-C4)アルキル、(C=O)O(C1-C4)アルキル及びフェニルから選択される1以上の置換基で置換されていても良い。 In another embodiment of formula I, A is selected from pyridine, pyrimidine, phenyl, pyridazine and pyrazine, respectively, independently (C 1 -C 6 ) alkyl, O (C 1 -C 6 ) alkyl, NR 7 Substituted with 1-3 R groups selected from R 8 , cyclobutyl, cyclopentyl, phenyl, morpholinyl, imidazolyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, triazolyl and tetrahydropyranyl, where each is independently halogen, CN, It may be substituted with one or more substituents selected from (C 1 -C 4 ) alkyl, (C = O) O (C 1 -C 4 ) alkyl and phenyl.
式Iの別の実施形態において、Aは、ピリジン、ピリミジン、フェニル、ピリダジン及びピラジンから選択され、それぞれ独立に(C1-C6)アルキル、O(C1-C6)アルキル、NR7R8、シクロブチル、シクロペンチル、フェニル、モルホリニル、イミダゾリル、ピラゾリル、オキサジアゾリル、ピロリジニル、トリアゾリル及びテトラヒドロピラニルから選択される1~2個のR基で置換され、ここで、それぞれは、独立にハロゲン、CN、(C1-C4)アルキル、(C=O)O(C1-C4)アルキル及びフェニルから選択される1以上の置換基で置換されていても良い。 In another embodiment of Formula I, A is selected from pyridine, pyrimidine, phenyl, pyridazine and pyrazine, independently (C1 - C6) alkyl, O (C1 - C6 ) alkyl, NR 7 R, respectively . 8. Substituted with 1-2 R groups selected from cyclobutyl, cyclopentyl, phenyl, morpholinyl, imidazolyl, pyrazolyl, oxadiazolyl, pyrrolidinyl, triazolyl and tetrahydropyranyl, where each is independently halogen, CN, It may be substituted with one or more substituents selected from (C 1 -C 4 ) alkyl, (C = O) O (C 1 -C 4 ) alkyl and phenyl.
式Iの別の実施形態において、R1はH又はメチルである。 In another embodiment of formula I, R 1 is H or methyl.
式Iの別の実施形態において、R2はH又はメチルである。 In another embodiment of formula I, R 2 is H or methyl.
式I又はIaの別の実施形態において、R3はH又はSi(CH3)3である。 In another embodiment of formula I or Ia, R 3 is H or Si (CH 3 ) 3 .
式I又はIaの別の実施形態において、R4はHである。 In another embodiment of formula I or Ia, R4 is H.
式Iの別の実施形態において、R3及びR4が一緒になって、シクロプロピル、シクロブチル、シクロペンチル又はシクロヘキシル環を形成していても良く、ここで、前記環は、独立にOH、ハロゲン又は(C1-C4)アルキルから選択される1以上の置換基で置換されていても良い。 In another embodiment of formula I, R 3 and R 4 may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring, where the rings are independently OH, halogen or It may be substituted with one or more substituents selected from (C 1 -C 4 ) alkyl.
式Iの別の実施形態において、R3及びR4が一緒になって、シクロプロピル、シクロブチル、シクロペンチル又はシクロヘキシル環を形成していても良い。 In another embodiment of Formula I, R 3 and R 4 may be combined to form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.
式Iの別の実施形態において、R5はH又はメチルである。 In another embodiment of formula I, R5 is H or methyl.
式Iの別の実施形態において、R6はH又はメチルである。 In another embodiment of formula I, R6 is H or methyl.
式Iの別の実施形態において、RaはH又はメチルである。 In another embodiment of formula I, Ra is H or methyl.
式Iの別の実施形態において、RbはH又はメチルである。 In another embodiment of formula I, R b is H or methyl.
式Iの別の実施形態において、R5はHである。 In another embodiment of formula I, R 5 is H.
式Iの別の実施形態において、R6はHである。 In another embodiment of formula I, R 6 is H.
式I又はIaの別の実施形態において、R7及びR8は、独立にH、(C1-C6)アルキル、(C3-C6)シクロアルキル及びフェニルから選択される。 In another embodiment of formula I or Ia, R7 and R8 are independently selected from H, (C1 - C6) alkyl , (C3 - C6 ) cycloalkyl and phenyl.
式I又はIaの別の実施形態において、R7及びR8は、独立にH、(C1-C6)アルキル、シクロペンチル及びフェニルから選択される。 In another embodiment of formula I or Ia, R7 and R8 are independently selected from H, (C1 - C6 ) alkyl, cyclopentyl and phenyl.
式Iの別の実施形態において、RaはHである。 In another embodiment of Formula I, Ra is H.
式Iの別の実施形態において、RbはHである。 In another embodiment of formula I, R b is H.
式Iの化合物において、原子がそれの天然同位体存在度を示す場合があり、又は、その原子のうちの1以上が同じ原子番号を有するが、天然において支配的に認められる原子質量もしくは質量数とは異なる原子質量もしくは質量数を有する特定の同位体を人為的に豊富とすることができる。本発明は、式Iの化合物の全ての好適な同位体型を含むことを意図する。例えば、水素(H)の異なる同位体型には、プロチウム(1H)及び重水素(2H又はD)を含む。プロチウムは、天然に認められる支配的な水素同位体である。重水素を豊富化することで、イン・ビボ半減期の増加又は必要投与量の削減などの治療上の利点が得られたり、生体サンプルの特性決定のための標準として有用な化合物が提供されることが可能となる。同位体豊富化された式Iに含まれる化合物は、当業者に公知の従来の技術により又は適切な同位体豊富化された試薬及び/又は中間体を用いて本明細書中の図式及び実施例に記載されている方法と類似の方法によって、過度の実験を行うことなく製造することができる。 In a compound of formula I, an atom may indicate its natural isotopic abundance, or one or more of its atoms have the same atomic number, but the atomic mass or mass number predominantly found in nature. Certain isotopes with different atomic masses or mass numbers can be artificially enriched. The present invention is intended to include all suitable isotope types of compounds of formula I. For example, different isotope types of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H or D). Protium is the dominant hydrogen isotope found in nature. Deuterium enrichment provides therapeutic benefits such as increased in vivo half-life or reduced dose requirements, and provides compounds that are useful as standards for characterization of biological samples. Is possible. The compounds contained in the isotope-enriched formula I are shown in the schemes and examples herein by conventional techniques known to those of skill in the art or using suitable isotope-enriched reagents and / or intermediates. It can be manufactured without undue experimentation by a method similar to the method described in.
反対のことが明瞭に記載されていない限り、本明細書で引用の全ての範囲は包括的である。例えば、「1~3個のヘテロ原子」を含むと記載されているヘテロアリール環は、その環が1、2又は3個のヘテロ原子を含むことができることを意味する。やはり理解すべき点として、本明細書で引用のあらゆる範囲が、それの範囲内にその範囲内の部分的範囲全てを包含することが理解される。ヘテロ原子N及びSの酸化された形態も、本発明の範囲に包含される。 The entire scope of the citations herein is inclusive unless the opposite is explicitly stated. For example, a heteroaryl ring described as containing "1 to 3 heteroatoms" means that the ring can contain 1, 2 or 3 heteroatoms. It is also to be understood that all scope of the citation herein includes all of the partial scope within that scope. Oxidized forms of heteroatoms N and S are also included within the scope of the invention.
多くの場合で、有機分子中の炭素原子がケイ素原子によって置き換わっていることで、類縁の安定な化合物を与え得ることは、当業者には明らかである。例えば、アルコキシ、アルキル、シクロアルキル、ヘテロアリール、複素環及びヒドロキシアルキル基における炭素原子は、多くの場合、ケイ素原子によって置き換わって安定な化合物を提供し得る。そのような化合物は全て、本発明の範囲に包含される。 It will be apparent to those skilled in the art that, in many cases, the replacement of carbon atoms in an organic molecule with silicon atoms can provide a stable compound of association. For example, carbon atoms in alkoxy, alkyl, cycloalkyl, heteroaryl, heterocycles and hydroxyalkyl groups can often be replaced by silicon atoms to provide stable compounds. All such compounds are within the scope of the invention.
任意の可変要素(例えば、R)が、任意の構成要素又は式I又は本発明の化合物を描き説明する任意の他の式に複数存在する場合、各場合でのそれの定義は、あらゆる他の場合でのそれの定義から独立である。更に、置換基及び/又は可変要素の組み合わせは、そのような組み合わせによって安定な化合物が得られる場合のみ許容される。 If any variable element (eg, R) is present in any component or in any other formula that depicts and describes formula I or the compounds of the invention, its definition in each case is any other. Independent of its definition in the case. Furthermore, combinations of substituents and / or variable elements are only allowed if such combinations provide stable compounds.
本発明の化合物のある種のものは不斉中心を有することができ、立体異性体の混合物として、又は個々のジアステレオマー若しくはエナンチオマーとして存在していることができる。単離されたものか混合物でのものかを問わず、これら化合物の全ての異性体型が、本発明の範囲に包含される。 Certain compounds of the invention can have asymmetric centers and can be present as a mixture of stereoisomers or as individual diastereomers or enantiomers. All isomer forms of these compounds, whether isolated or in mixtures, are included within the scope of the invention.
本発明の化合物のある種のものは、互変異性体として存在し得る。本発明の目的のため、式Iの化合物についての言及は、その化合物自体又はそれの互変異性体自体のいずれか、又は2以上の互変異性体の混合物についての言及である。 Certain compounds of the invention may exist as tautomers. For the purposes of the present invention, reference to a compound of formula I is any reference to either the compound itself or its tautomer itself, or a mixture of two or more tautomers.
本発明の化合物は、アルツハイマー病の予防、治療又は改善において有用性を有し得る。当該化合物は、α7nAChRが介在する他の疾患、例えば統合失調症、睡眠障害、パーキンソン病、自閉症、微小欠失症候群、炎症疾患、疼痛性障害(急性疼痛、炎症性痛覚及び神経障害痛を含む)及び認知障害(軽度認知機能障害を含む)を予防、治療又は改善する上でも有用であり得る。本発明の化合物によって予防、治療又は改善し得る他の症状には、肺高血圧、慢性閉塞性肺疾患(COPD)、喘息、尿失禁、緑内障、トリソミー21(ダウン症候群)、脳アミロイド血管症、変性認知症、オランダ型のアミロイドーシスを伴う遺伝性大脳出血(HCHWA-D)、クロイツフェルト・ヤコブ疾患、プリオン病、筋萎縮性側索硬化症、進行性核上性麻痺、頭部外傷、卒中、膵炎、封入体筋炎、他の末梢アミロイドーシス、糖尿病、腎臓疾患、がん及びアテローム性動脈硬化症を含む。 The compounds of the present invention may have utility in the prevention, treatment or amelioration of Alzheimer's disease. The compound may cause other disorders mediated by α7nAChR, such as schizophrenia, sleep disorders, Parkinson's disease, autism, microdeletion syndrome, inflammatory disorders, pain disorders (acute pain, inflammatory pain sensation and neuropathy pain). It may also be useful in preventing, treating or ameliorating cognitive impairment (including mild cognitive dysfunction). Other symptoms that can be prevented, treated or ameliorated by the compounds of the invention include pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, trisomy 21 (Down's syndrome), cerebral amyloid angiopathy, dementia. Dementia, hereditary cerebral hemorrhage with Dutch amyloidosis (HCHWA-D), Kreuzfeld-Jakob disease, prion disease, muscular atrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis , Inclusion body myositis, other peripheral amyloidosis, diabetes, kidney disease, cancer and atherosclerosis.
好ましい実施態様において、本発明の化合物はアルツハイマー病、認知障害、統合失調症、疼痛障害及び睡眠障害の予防、治療若しくは改善において有用である。例えば、その化合物は、アルツハイマー型認知症を予防、並びにアルツハイマー型の早期、中期又は後期認知症の治療において有用となり得る。 In a preferred embodiment, the compounds of the invention are useful in the prevention, treatment or amelioration of Alzheimer's disease, cognitive disorders, schizophrenia, pain disorders and sleep disorders. For example, the compound may be useful in the prevention of Alzheimer's disease and in the treatment of early, middle or late Alzheimer's disease.
本発明の化合物が有用となり得る可能性がある統合失調症症状又は障害には、統合失調症(妄想型、解体型、緊張型又は未分化型)、統合失調症様障害、統合失調性感情障害、妄想性障害、短期精神異常、共有精神異常、全身状態並びに物質誘発性及び薬剤誘発性(フェンシクリジン、ケタミン及び他の解離性麻酔薬、アンフェタミン及び他の覚醒剤並びにコカイン)精神異常による精神異常、情動障害に関連する精神病、短期反応精神病、統合失調性精神病、分裂性又は統合失調症性人格障害のような「統合失調症圏障害」、又は統合失調症及び他の精神病の陽性及び陰性の両方の徴候を含む精神病に関連する病気(大鬱病、躁鬱病(双極性障害)、アルツハイマー病及び心的外傷後ストレス症候群など)を含む統合失調症及び精神病;認知症(アルツハイマー病、虚血、多発脳梗塞性認知症、外傷、血管の問題若しくは卒中、HIV疾患、パーキンソン病、ハンチントン病、ピック病、クロイツフェルト・ヤコブ病、周生期低酸素症、他の全身症状又は薬物乱用に関連する)を含む認知障害;譫妄、健忘障害又は加齢関連の認識衰退という症状又は疾患のうちの1以上を含む。 The schizophrenia symptoms or disorders in which the compounds of the present invention may be useful include schizophrenia (delusional, disassembled, tensioned or undifferentiated), schizophrenia-like disorders, schizophrenia emotional disorders. , Delusional disorders, short-term psychiatric disorders, shared psychiatric disorders, general conditions and substance-induced and drug-induced (fencyclidine, ketamine and other dissecting anesthetics, amphetamines and other stimulants and cocaine) psychiatric disorders , Psychiatric disorders associated with emotional disorders, short-term reaction psychiatric disorders, schizophrenia psychiatric disorders, schizophrenia or schizophrenia psychiatric disorders such as schizophrenia personality disorders, or positive and negative psychiatric disorders and other psychiatric disorders Psychiatric disorders and psychiatric disorders including psychotic disorders including both signs (major depression, manic depression (bipolar disorder), Alzheimer's disease and post-traumatic stress syndrome, etc.); dementia (Alzheimer's disease, ischemia, etc.) Multiple cerebral infarction dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Kreuzfeld-Jakob's disease, perinatal hypoxia, other systemic symptoms or related to drug abuse) Cognitive Disorders Including: One or more of the symptoms or disorders of psychiatric disorders, forgetfulness disorders or age-related cognitive decline.
従って、別の具体的な実施形態において本発明は、処置を必要とする患者に対して有効量の本発明の化合物を投与することを含む、統合失調症又は精神病の予防、治療若しくは改善方法を提供する。現在、精神障害診断統計マニュアル再版(Diagnostic and Statistical Manual of Mental Disorders:DSM-IV-TR)の第4版の(2000,American Psychiatric Association,Washington DC)には、妄想性、解体型、緊張型又は未分化型の統合失調症及び物質誘発精神異常を含む診断手段が提供されている。本明細書で使用される場合、「統合失調症及び精神病」という用語は、DSM-IV-TRに記載の精神障害の治療を含む。精神障害についての別の命名法、疾病分類及び分類システムがあること、そしてそれらのシステムが医学及び科学の発達に伴って進化することは、当業者には明らかであろう。従って、「統合失調症又は精神病」という用語は、他の診断情報源に記載されている同様の障害を包含することを意図する。 Accordingly, in another specific embodiment, the present invention provides a method for preventing, treating or ameliorating schizophrenia or psychosis, which comprises administering an effective amount of a compound of the present invention to a patient in need of treatment. offer. Currently, the 4th edition of the Digital and Statistical Manual Disorderers (DSM-IV-TR) (2000, American Psychiatric Assistance, Delusion, Wasington DC) Diagnostic tools are provided that include undifferentiated schizophrenia and substance-induced psychiatric disorders. As used herein, the term "schizophrenia and psychosis" includes the treatment of mental disorders as described in DSM-IV-TR. It will be clear to those skilled in the art that there are other nomenclatures, disease classifications and classification systems for mental illness, and that those systems evolve with the development of medicine and science. Therefore, the term "schizophrenia or psychosis" is intended to include similar disorders described in other diagnostic sources.
本発明の化合物が有用となり可能性がある睡眠症状又は睡眠障害には、睡眠の質の強化;睡眠の質の向上;睡眠維持の延長;対象者が眠っている時間を対象者が眠ろうと試みた時間で割って計算される値の上昇;睡眠の待ち時間又は開始(寝入るのにかかる時間)の短縮;寝入り困難の減少;睡眠連続性の増加;睡眠中に覚醒する回数の減少;夜間覚醒の減少;就寝開始から覚醒状態で過ごす時間の短縮;全睡眠量の増加;睡眠の断片化の減少;REM睡眠期間のタイミング、回数又は長さの変更;徐波(すなわち、段階3又は4)睡眠期間のタイミング、頻度又は長さの変更;ステージ2睡眠の量及びパーセントの増加;徐波睡眠の促進;睡眠中のEEG-デルタ活性の強化;昼間敏活性の向上;昼間傾眠の低下;過度の昼間眠気の治療又は抑制;不眠;過眠症;ナルコレプシー;睡眠の中断;睡眠時無呼吸;覚醒;夜間ミオクロヌス;REM睡眠中断;時差ぼけ;交替勤務者の睡眠障害;睡眠異常;夜鷹症;抑鬱、情緒障害/気分障害並びに夢遊病及び夜尿症に関連する不眠、そして老化に伴う睡眠障害;アルツハイマーの日暮れ時兆候;概日リズムに関連する症状、並びに時間帯を通過する旅行及び交替勤務スケジュールに関連する精神的及び肉体的障害;副作用としてREM睡眠を減少させる薬物に起因する症状;体力回復のない睡眠及び筋肉痛により発現される症候群、又は睡眠中の呼吸異常に関連する睡眠時無呼吸;及び睡眠の質の低下により生ずる症状を含む。 For sleep symptoms or disorders in which the compounds of the present invention may be useful, sleep quality enhancement; sleep quality improvement; sleep maintenance prolongation; subject attempts to sleep during sleep time. Increased value calculated by dividing by time; shorter waiting time or start of sleep (time to fall asleep); less difficulty falling asleep; increased sleep continuity; less frequent awakenings during sleep; nocturnal awakening Reduced; reduced time spent awake from bedtime; increased total sleep; reduced sleep fragmentation; altered timing, frequency or length of REM sleep period; slow wave (ie, stage 3 or 4) Changes in timing, frequency or length of sleep period; increased amount and percentage of stage 2 sleep; promotion of slow-wave sleep; enhanced EEG-delta activity during sleep; increased daytime agility; decreased daytime sleepiness; excessive Treatment or suppression of daytime sleepiness; insomnia; hypersomnia; narcolepsy; sleep interruption; sleep apnea; arousal; nocturnal myochronus; REM sleep interruption; staggered; shift worker sleep disorders; sleep abnormalities; night hawk disease; Depression, emotional / mood disorders and sleeplessness associated with dreamy and nocturnal illness, and sleep disorders associated with aging; Alzheimer's nightfall signs; Related mental and physical disorders; Symptoms caused by drugs that reduce REM sleep as side effects; Syndromes manifested by sleep without recovery and muscle pain, or sleep apnea associated with respiratory abnormalities during sleep; And symptoms caused by poor sleep quality.
本発明の化合物が有用となり得る疼痛障害には、神経因性疼痛(帯状疱疹後神経痛、神経損傷、「ジニア」(例:外陰部痛)、幻肢痛、神経根引き抜き損傷、有痛性糖尿病性神経障害、有痛性外傷単神経障害、有痛性多発性神経障害など);中枢痛症候群(実質的に神経系のあらゆるレベルでのあらゆる病変によって生じる可能性がある);術後痛症候群(例:乳房切除術後症候群、開胸術後症候群、断端痛);骨及び関節痛(骨関節炎)、反復運動痛、歯痛、がん痛、筋筋膜痛(筋肉損傷、線維筋痛);術中痛(一般手術、婦人科手術)、慢性痛、月経困難症、並びに狭心症関連の疼痛及び異なる起源の炎症性疼痛(例:骨関節炎、関節リウマチ、リウマチ性疾患、腱鞘炎及び痛風)、頭痛、片頭痛及び群発頭痛、一次痛覚過敏、二次痛覚過敏、一次アロディニア、二次アロディニア、或いは中枢感作によって生じる他の疼痛を含む。 Pain disorders in which the compounds of the present invention may be useful include neuropathic pain (post-herpes zoster nerve pain, nerve injury, "genia" (eg, genital pain), phantom limb pain, nerve root withdrawal injury, painful diabetes. Sexual neuropathy, painful traumatic mononeuropathy, painful multiple neuropathy, etc.); Central pain syndrome (which can be caused by virtually any lesion at any level of the nervous system); postoperative pain syndrome (Example: post-mammectomy syndrome, post-open chest syndrome, stump pain); bone and joint pain (osteoarthritis), repetitive exercise pain, tooth pain, cancer pain, myofascial pain (muscle injury, fibromyalgia) ); Intraoperative pain (general surgery, gynecological surgery), chronic pain, difficulty menstruating, and angina-related pain and inflammatory pain of different origin (eg osteoarthritis, rheumatoid arthritis, rheumatic disease, tendonitis and gout) ), Headache, migraine and swarm headache, primary pain hypersensitivity, secondary pain hypersensitivity, primary allodynia, secondary allodynia, or other pain caused by central sensitization.
本発明の化合物が有用であり得る強い炎症構成を有する可能性のある症状又は障害には、次の症状又は障害:糖尿病(インシュリン耐性を生じさせ得るIL-6及びTNFαなどの血中サイトカイン類の増加を特徴とする糖尿病における全身炎症);喘息;関節炎;嚢胞性線維症;敗血症;潰瘍性大腸炎;炎症性大腸炎;アテローム性動脈硬化;神経変性疾患(例えば、アルツハイマー病、パーキンソン病、クロイツフェルト・ヤコブ病、前頭側頭認知症、大脳皮質基底核変性症、ピック病、進行性核上まひ、外傷性脳損傷、ハンチントン病、筋萎縮性側索硬化症)に関連する神経炎症のうちの1以上を含む。 Symptoms or disorders that may have a strong inflammatory composition in which the compounds of the invention may be useful include the following symptoms or disorders: Diabetes (blood cytokines such as IL-6 and TNFα that can cause insulin resistance). Systemic inflammation in diabetes characterized by increased); asthma; arthritis; cystic fibrosis; sepsis; ulcerative colitis; inflammatory colitis; atherosclerosis; neurodegenerative diseases (eg, Alzheimer's disease, Parkinson's disease, Kreuz) Of the neuroinflammations associated with Felt-Jakob's disease, frontotemporal dementia, cerebral cortical basal nuclear degeneration, Pick's disease, progressive nuclear paralysis, traumatic brain injury, Huntington's disease, muscular atrophic lateral sclerosis) Includes 1 or more of.
本発明の化合物は、運動障害を治療若しくは予防若しくは改善し、そしてパーキンソン病における黒質線条体ニューロンでの神経変性に対して保護を行うのに用いることもできる。さらに、本発明の化合物は、疼痛のオピオイド治療に対する耐性及び/又は依存性を低下させたり、そして、例えばアルコール、オピオイド類及びコカインの禁断症候群を治療するのに用いることができる。 The compounds of the present invention can also be used to treat, prevent or ameliorate movement disorders and to provide protection against neurodegeneration in substantia nigra striatal neurons in Parkinson's disease. In addition, the compounds of the invention can be used to reduce tolerance and / or dependence of pain on opioid treatment and, for example, to treat withdrawal syndromes of alcohol, opioids and cocaine.
本発明の化合物は、薬学的に許容される塩の形態で投与することができる。「薬学的に許容される塩」という用語は、親化合物の有効性を保有し、生物学的又は他の点で望ましくないものではない(例えば、その被投与者にとって毒性でなく、他の点でも有害でない)塩を指す。好適な塩には、例えば本発明の化合物の溶液を塩酸、硫酸、酢酸、トリフルオロ酢酸又は安息香酸のような薬学的に許容される酸の溶液と混合することによって形成することのできる酸付加塩が含まれる。本発明の化合物の多くが酸性部分を有しており、その場合、それの好適な薬学的に許容される塩には、アルカリ金属塩(例えば、ナトリウム又はカリウム塩)、アルカリ土類金属塩(例えば、カルシウム又はマグネシウム塩)、及び第四級アンモニウム塩のような好適な有機リガンドと形成される塩を含む。さらに、酸基(-COOH)又はアルコール基が存在する場合、薬学的に許容されるエステルを用いてその化合物の溶解度又は加水分解特性を変えることができる。 The compounds of the invention can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" retains the efficacy of the parent compound and is not biologically or otherwise undesirable (eg, not toxic to its recipient and is otherwise). (But not harmful) refers to salt. Suitable salts are acid additions that can be formed, for example, by mixing a solution of a compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or benzoic acid. Contains salt. Many of the compounds of the invention have an acidic moiety, in which case suitable pharmaceutically acceptable salts thereof include alkali metal salts (eg, sodium or potassium salts), alkaline earth metal salts (eg, sodium or potassium salts). For example, calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts. In addition, if an acid group (-COOH) or alcohol group is present, a pharmaceutically acceptable ester can be used to alter the solubility or hydrolysis properties of the compound.
酸付加塩の例には、酢酸塩、アスコルビン酸塩、安息香酸塩、ベンゼンスルホン酸塩、重硫酸塩、ホウ酸塩、酪酸塩、クエン酸塩、樟脳酸塩、カンファースルホン酸塩、フマル酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、乳酸塩、マレイン酸塩、メタンスルホン酸塩(「メシレート」)、ナフタレンスルホン酸塩、硝酸塩、シュウ酸塩、リン酸塩、プロピオン酸塩、サリチル酸塩、コハク酸塩、硫酸塩、酒石酸塩、チオシアン酸塩、トルエンスルホン酸塩(トシレートとも称される)などを含む。さらに、塩基性医薬化合物からの医薬的に有用な塩の形成に好適であると一般に考えられる酸については、例えばP. Stahl et al, Camille G. (編者) Handbook of Pharmaceutical Salt.Properties, Selection and Use. (2002) Zurich: Wiley-VCH;S. Berge et al、Journal of Pharmaceutical Sciences (1977)66(1)1-19;P. Gould, International J. of Pharmaceutics (1986) 33 201-217;Anderson et al、The Practice of Medicinal Chemistry(1996), Academic Press, New York;およびThe Orange Book (Food & Drug Administration, Washington, D.C.、ウェブサイトで)に記載されている。 Examples of acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bicarbonate, borate, butyrate, citrate, sulphonate, camphorsulfonate, fumaric acid. Salt, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate (“mesylate”), naphthalene sulfonate, nitrate, oxalate, phosphate, propion Includes acid salts, salicylates, succinates, sulfates, tartrates, thiosocyanates, toluenessulfonates (also called tosylate) and the like. Further, for acids generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds, see, for example, P.I. Stahl et al, Camille G. et al. (Editor) Handbook of Physical Salt. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S.A. Berge et al, Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; P.M. Gold, International J.M. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medical Chemistry (1996), Academic Press, New York; and The Online; It is described in.
塩基性塩の例には、アンモニウム塩、ナトリウム、リチウム及びカリウム塩のようなアルカリ金属塩、カルシウム及びマグネシウム塩のようなアルカリ土類金属塩、ジシクロヘキシルアミン、t-ブチルアミン、コリンのような有機塩基(例えば、有機アミン)との塩、及びアルギニン、リジンのようなアミノ酸との塩を含む。塩基性窒素含有基は、低級アルキルハライド(例えば、塩化、臭化及びヨウ化メチル、エチル及びブチル)、硫酸ジアルキル(例えば、硫酸ジメチル、ジエチル及びジブチル)、長鎖ハライド(例えば、塩化、臭化及びヨウ化デシル、ラウリル及びステアリル)、アラルキルハライド(例えば、臭化ベンジル及びフェネチル)及びその他などの薬剤で四級化することができる。 Examples of basic salts include alkali metal salts such as ammonium salts, sodium, lithium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, organic bases such as dicyclohexylamine, t-butylamine, choline. Includes salts with (eg, organic amines) and salts with amino acids such as arginine, lysine. Basic nitrogen-containing groups include lower alkyl halides (eg, chloride, bromide and methyl iodide, ethyl and butyl), dialkyl sulfates (eg, dimethyl sulfate, diethyl and dibutyl), long chain halides (eg, chloride, bromide). And can be quaternized with agents such as decyl iodide, lauryl and stearyl), aralkyl halides (eg, benzyl bromide and phenethyl) and others.
アルツハイマー病、パーキンソン病、統合失調症、L-DOPA誘発運動障害及び炎症における認知機能障害を予防、治療又は改善するために、塩の形態であっても良い本発明の化合物は、活性薬剤をその薬剤の作用部位と接触させる任意の手段によって投与することができる。それらは、個々の治療剤として又は治療剤の組み合わせとして、医薬品との併用に使用可能な1以上の従来の手段によって投与することができる。それらは単独で投与することができるが、代表的には選択される投与経路及び標準的な医薬上の実務に基づいて選択される医薬担体とともに投与される。本発明の化合物は、例えば経口投与、非経口投与(皮下注射、静脈、筋肉、胸骨内の注射又は注入法を含む)、吸入(噴霧剤形態など)又は直腸投与のうちの1以上によって、有効量の当該化合物並びに従来の無毒性の薬学的に許容される担体、補助剤及び媒体を含む単位用量の医薬組成物の形態で投与することができる。経口投与に好適な液体製剤(例えば、懸濁液、シロップ、エリキシル剤など)は、当業界で公知の技術に従って調製することができ、水、グリコール類、オイル類、アルコール類のような通常の媒体のいずれかを用いることができる。経口投与に好適な固体製剤(例えば、粉剤、丸薬、カプセル及び錠剤)は、当業界で公知の技術に従って製造することができ、デンプン類、糖類、カオリン、滑沢剤、結合剤、崩壊剤のような固体賦形剤を用いることができる。非経口組成物は、当業界で公知の技術に従って製造することができ、代表的には担体としての無菌水及び場合により溶解補助剤のような他の成分を用いる。注射用溶液は当業界で公知の技術に従って製造することができ、担体には生理食塩水溶液、グルコース溶液又は生理食塩水とグルコースの混合物を含む溶液を含む。本発明の医薬組成物の製造での使用に好適な方法並びに前記組成物での使用に好適な成分についてのさらなる説明は、(Remington′s Pharmaceutical Sciences, 18th edition(ed. A. R. Genaro, Mack Publishing Co., 1990)で提供される。 To prevent, treat or ameliorate cognitive dysfunction in Alzheimer's disease, Parkinson's disease, schizophrenia, L-DOPA-induced movement disorders and inflammation, the compounds of the invention, which may be in the form of salts, are active agents thereof. It can be administered by any means of contact with the site of action of the drug. They can be administered by one or more conventional means that can be used in combination with pharmaceuticals, either as individual therapeutic agents or as a combination of therapeutic agents. They can be administered alone, but are typically administered with a route of administration of choice and a pharmaceutical carrier selected based on standard pharmaceutical practices. The compounds of the present invention are effective, for example, by one or more of oral administration, parenteral administration (including subcutaneous injection, intravenous, muscle, intrathoracic injection or infusion method), inhalation (spraying form, etc.) or rectal administration. It can be administered in the form of a unit dose pharmaceutical composition comprising an amount of the compound as well as conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Liquid formulations suitable for oral administration (eg, suspensions, syrups, elixirs, etc.) can be prepared according to techniques known in the art and are common such as water, glycols, oils, alcohols. Any of the media can be used. Solid formulations suitable for oral administration (eg, powders, pills, capsules and tablets) can be produced according to techniques known in the art for starches, sugars, kaolins, lubricants, binders, disintegrants. Such solid excipients can be used. Parenteral compositions can be prepared according to techniques known in the art, typically using sterile water as a carrier and optionally other components such as lysis aids. The solution for injection can be produced according to a technique known in the art, and the carrier includes an aqueous solution of physiological saline, a glucose solution, or a solution containing a mixture of physiological saline and glucose. Further description of methods suitable for use in the manufacture of the pharmaceutical compositions of the present invention and ingredients suitable for use in said compositions is described in (Remington's Pharmaceutical Sciences, 18th edition (ed. A. R. Genaro ). , Mack Publishing Co., 1990).
本発明の化合物は、0.001~1000mg/kg(哺乳動物(例えば、ヒト)体重)/日の用量範囲で、単回投与又は分割投与にて経口投与することができる。ある用量範囲は、経口の単回投与又は分割投与にて0.01~500mg/kg体重/日である。別の用量範囲は、経口投与で単回投与又は分割投与にて0.01~100mg/kg体重/日である。経口投与の場合、処置を受ける患者に対する用量の症候的調節のために1.0~500mgの有効成分、特には1、5、10、15、20、25、50、75、100、150、200、250、300、400及び500mgの有効成分を含む錠剤又はカプセルの形態で組成物を提供することができる。特定の患者についての具体的な用量レベル及び投与回数は変動し得るものであり、使用される具体的な化合物の活性、その化合物の代謝安定性及び作用期間、年齢、体重、全身の健康状態、性別、食事、投与の形態及び時刻、排泄速度、併用薬剤及び特定の症状の重度を含む各種要素に依存しよう。 The compounds of the present invention can be orally administered in single doses or divided doses in a dose range of 0.001 to 1000 mg / kg (mammalian (eg, human) body weight) / day. One dose range is 0.01-500 mg / kg body weight / day in single or divided doses. Another dose range is 0.01-100 mg / kg body weight / day for single or divided doses by oral administration. In the case of oral administration, 1.0-500 mg of active ingredient, especially 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200 for symptomatic dose adjustment to the treated patient. , 250, 300, 400 and 500 mg of the active ingredient can be provided in the form of tablets or capsules. Specific dose levels and frequency of administration for a particular patient can vary and the activity of the specific compound used, metabolic stability and duration of action of the compound, age, body weight, general health, It will depend on various factors including gender, diet, mode and time of administration, rate of excretion, concomitant medications and severity of specific symptoms.
上記のように、本発明は、1以上の治療剤と組み合わせた本発明の化合物、並びに、本発明の化合物、及び、抗アルツハイマー病薬、例えばβ-セクレターゼ阻害剤、例えばベルベセスタット;M1mAChR作動薬又はPAM;M4mAChR作動薬又はPAM;mGluR2拮抗薬又はNAM又はPAM;ADAM10リガンド又は活性化剤;γ-セクレターゼ阻害剤、例えばLY450139及びTAK070;γ-セクレターゼ調節剤;τ-リン酸化阻害剤;グリシン輸送阻害剤;LXRβ作動薬;ApoE4コンフォメーション調節剤;NR2B拮抗薬;アンドロゲン受容体調節剤;Αβオリゴマー形成の遮断薬;5-HT4作動薬、例えばPRX-03140;5-HT6拮抗薬、例えばGSK742467、SGS-518、FK-962、SL-65.0155、SRA-333及びキサリプロデン;5-HT1a拮抗薬、例えばレコゾタン;p25/CDK5阻害剤;NK1/NK3受容体拮抗薬;COX-2阻害剤;LRRK2阻害剤;HMG-CoAレダクターゼ阻害剤;イブプロフェンなどのNSAID類;ビタミンE;抗アミロイド抗体(抗アミロイドヒト化モノクローナル抗体など)、例えばバピネオズマブ、ACC001、CAD106、AZD3102、H12A11V1;抗炎症化合物、例えば(R)-フルルビプロフェン、ニトロフルルビプロフェン、ND-1251、VP-025、HT-0712及びEHT-202;PPARγ作動薬、例えばピオグリタゾン及びロシグリタゾン;CB-1受容体拮抗薬又はCB-1受容体逆作動薬、例えばAVE1625;抗生物質、例えばドキシサイクリン及びリファンピン;N-メチル-D-アスパラギン酸(NMDA)受容体拮抗薬、例えばメマンチン、ネラメキサン及びEVT101;コリンエステラーゼ阻害剤、例えばガランタミン、リバスティグミン、ドネペジル、タクリン、フェンセリン、ラドスチギル及びABT-089;成長ホルモン分泌促進因子、例えばイブタモレン、イブタモレン・メシレート及びカプロモレリン(capromorelin);ヒスタミンH3受容体拮抗薬、例えばABT-834、ABT829、GSK189254及びCEP16795;AMPA作動薬又はAMPA調節剤、例えばCX-717、LY451395、LY404187及びS-18986;PDEIV阻害剤、例えばMEM1414、HT0712及びAVE8112;GABAA逆作動薬;GSK3阻害剤、例えばAZD1080、SAR502250及びCEP16805;神経細胞ニコチン作動薬;選択的M1作動薬;HDAC阻害剤;及び微小管親和性調節キナーゼ(MARK)リガンド;又は本発明の化合物の効力、安全性、簡便性を高めるか、若しくは望ましくない副作用若しくは毒性を低減させる、受容体若しくは酵素に影響する他の薬剤からなる群から選択される1以上の治療剤を含む医薬組成物、を用いる、アルツハイマー病、パーキンソン病、統合失調症、L-DOPA誘発運動障害及び炎症での認知機能障害の予防、治療若しくは改善方法に関するものでもある。 As described above, the invention relates to the compounds of the invention in combination with one or more therapeutic agents, as well as the compounds of the invention and anti-Alzheimer's disease agents such as β-secretase inhibitors such as velvecestat; M1 mAChR activation. Drugs or PAMs; M4mAChR agonists or PAMs; mGluR2 antagonists or NAMs or PAMs; ADAM10 ligands or activators; γ-secretase inhibitors such as LY450139 and TAK070; γ-secretase regulators; τ-phosphorylation inhibitors; glycine Transport inhibitor; LXRβ agonist; ApoE4 conformation regulator; NR2B antagonist; androgen receptor regulator; Αβ oligomer formation blocker; 5-HT4 agonist, eg PRX-03140; 5-HT6 antagonist, eg GSK742467 , SGS-518, FK-962, SL-65.0155, SRA-333 and xaliproden; 5-HT1a antagonists such as recozotan; p25 / CDK5 inhibitor; NK1 / NK3 receptor antagonist; COX-2 inhibitor; LRRK2 inhibitor; HMG-CoA reductase inhibitor; NSAIDs such as ibprofen; Vitamin E; anti-amyloid antibody (anti-amyloid humanized monoclonal antibody, etc.), such as bapineozumab, ACC001, CAD106, AZD3102, H12A11V1; R) -flurubiprofen, nitroflurubiprofen, ND-1251, VP-025, HT-0712 and EHT-202; PPARγ agonists such as pioglitazone and rosiglitazone; CB-1 receptor antagonists or CB- 1 Receptor reverse agonists such as AVE1625; antibiotics such as doxicycline and riphanpin; N-methyl-D-aspartic acid (NMDA) receptor antagonists such as memantin, nelamexan and EVT101; cholineresterase inhibitors such as galantamine, rivastig Min, Donepezil, Tacrine, Fencelin, Radostigil and ABT-089; Growth hormone secretagogues such as ibutamolen, ibutamoren mesylate and capromolelin; histamine H3 receptor antagonists such as ABT-834, ABT829, GSK189 AMPA agonists or AMPA regulators such as CX-717, LY451395, LY404187 and S-18896; PDEIV inhibitors such as MEM 1414, HT0712 and AVE8112; GABAA reverse agonists; GSK3 inhibitors such as AZD1080, SAR502250 and CEP16805; nerve cell nicotine agonists; selective M1 agonists; HDAC inhibitors; and microtube affinity regulatory kinase (MARK) ligands; Alternatively, one or more therapeutic agents selected from the group consisting of other agents that affect the receptor or enzyme that enhance the efficacy, safety, convenience of the compounds of the invention, or reduce unwanted side effects or toxicity. It also relates to a method for preventing, treating or ameliorating cognitive dysfunction in Alzheimer's disease, Parkinson's disease, schizophrenia, L-DOPA-induced motor impairment and inflammation using the pharmaceutical composition containing the above.
本発明の化合物の組み合わせの例には、統合失調症の治療のための薬剤との組み合わせ、例えば鎮静剤、睡眠薬、精神安定剤、抗精神病薬、抗不安薬、シクロピロロン、イミダゾピリジン、ピラゾロピリミジン、マイナートランキライザー、メラトニン作動薬および拮抗薬、メラトニン作動薬、ベンゾジアゼピン、バルビツレート、5HT-2拮抗薬など、例えば:アジナゾラム、アロバルビタール、アロニミド、アルプラゾラム、アミスルプリド、アミトリプチリン、アモバルビタール、アモキサピン、アリピプラゾール、ベンタゼパム、ベンゾクタミン、ブロチゾラム、ブプロピオン、ブスプリオン、ブタバルビタール、ブタルビタール、カプリド、カルボクロラール、クロラールベタイン、抱水クロラール、クロミプラミン、クロナゼパム、クロペリドン、クロラゼパート、クロルジアゼポキシド、クロレタート(clorethate)、クロルプロマジン、クロザピン、シプラゼパム、デシプラミン、デキスクラモール、ジアゼパム、ジクロラールフェナゾン、ジバルプロエクス、ジフェンヒドラミン、ドキセピン、エスタゾラム、エスクロルビノール、エトミダート、フェノバム、フルニトラゼパム、フルペンチキソール、フルフェナジン、フルラゼパム、フルボキサミン、フルオキセチン、ホサゼパム、グルテチミド、ハラゼパム、ハロペリドール、ヒドロキシジン、イミプラミン、リチウム、ロラゼパム、ロルメタゼパム、マプロチリン、メクロカロン、メラトニン、メホバルビタール、メプロバメート、メタカロン、ミダフルル、ミダゾラム、ネファゾドン、ニソバマート、ニトラゼパム、ノルトリプチリン、オランザピン、オキサゼパム、パラアルデヒド、パロキセチン、ペントバルビタール、ペルラピン、ペルフェナジン、フェネルジン、フェノバルビタール、プラゼパム、プロメタジン、プロポフォール、プロトリプチリン、クアゼパム、クエチアピン、レクラゼパム、リスペリドン、ロレタミド、セコバルビタール、セルトラリン、スプロエロン(suproelone)、テマゼパム、チオリダジン、チオチキセン、トラカゾレート、トラニルシプロマイン(tranylcypromaine)、トラゾドン、トリアゾラム、トレピパム、トリセタミド、トリクロホス、トリフルオロペラジン、トリメトジン、トリミプラミン、ウルダゼパム、ベンラファキシン、ザレプロン、ジプラシドン、ゾラゼパム、ゾルピデムおよびこれらの塩、並びにそれらの組み合わせなどとの組み合わせを含み、或いは、本発明の化合物は、光療法または電気刺激などの物理的方法の使用と併せて投与することができる。 Examples of compound combinations of the present invention include combinations with agents for the treatment of schizophrenia, such as sedatives, sleeping pills, tranquilizers, antipsychotics, antidepressants, cyclopyrrone, imidazole pyridine, pyrazolo. Pyrimidin, minor tranquilizers, melatonin agonists and antagonists, melatonin agonists, benzodiazepoxide, barbitalate, 5HT-2 antagonists, etc. , Benzoctamine, Brothizolam, Bupropion, Busprion, Butabarbital, Butalbital, Caprid, Carbochloral, Chloralbetaine, Chloral hydrate, Chloralzepoxide, Chloralzepoxide, Chloralidone, Chlorazepoxide, Chlordiazepoxide, Chlordiazepoxide, Chlordiazepoxide, Clorethine Dexclamol, diazepam, dichloral phenazone, givalproex, diphenhydramine, doxepin, estazolam, eschlorbinol, etomidat, phenovam, flunitrazepam, fullpentixol, flufenazine, flulazepam, fulboxamine, fluoxetine, hosazepam , Haloperidol, Hydroxyzine, Imipramine, Lithium, Lorazepam, Lolmetazepam, Maplotyrin, Mecrocaron, Melatonin, Mehobarbital, Meprobamate, Metacaron, Midafuru, Midazolam, Nefazodon, Nisobamart, Nitrazepam, Nortryptiline, , Perlapine, perphenazine, phenergine, phenobarbital, placepam, promethazine, propofol, protryptyrin, quazepam, quetiapin, leclazepam, risperidone, loletamide, secobarbital, sertraline, suproelone, suproelone, sproelone Lucipromine, trazodon, triazolam, trepipam, trisetamide, triclophos, trifluoroperazine, trimetidine, trimipramine, uldazepam, benrafaxin, zarepron, ziplacidone , Zolazepam, zolpidem and salts thereof, and combinations thereof, etc., or the compounds of the invention can be administered in conjunction with the use of physical methods such as phototherapy or electrical stimulation.
別の実施形態において、本発明の化合物は、レボドパ(カルビドパ又はベンセラジドのような選択的脳外デカルボキシラーゼ阻害剤と合わせて又はそれと合わせず)、抗コリン作動薬、例えばビペリデン(適宜に、それの塩酸塩又は乳酸塩として)及びトリヘキシフェニジル(ベンズヘキソール)塩酸塩、COMT阻害剤、例えばエンタカポン、MAO-B阻害剤、抗酸化剤、A2aアデノシン受容体拮抗薬、コリン作動性作動薬、NMDA受容体拮抗薬、セロトニン受容体拮抗薬及びドーパミン受容体作動薬、例えばアレンテモール、ブロモクリプチン、フェノルドパム、リスリド、ナキサゴリド、ペルゴリド及びプラミぺキソールと併用することができる。ドーパミン作動薬が、医薬として許容される塩、例えばアレンテモール臭化水素酸塩、メシル酸ブロモクリプチン、メシル酸フェノルドパム、ナキサゴリド塩酸塩及びメシル酸ペルゴリドの形態であり得ることは明らかであろう。 In another embodiment, the compounds of the invention are levodopa (with or without selective intracerebral decarboxylase inhibitors such as carbidopa or venceradide), anticholinergic agonists such as viperidene (as appropriate, of it). (As hydrochloride or lactate) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MAO-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, It can be used in combination with NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocryptin, phenodopam, lislide, naxagolide, pergoride and pramipexol. It will be clear that the dopamine agonist may be in the form of pharmaceutically acceptable salts such as alentemol hydrobromide, bromocriptine mesylate, phenodpam mesylate, naxagolide hydrochloride and pergolide mesylate.
別の実施形態において、本発明の化合物は、フェノチアジン、チオキサンテン、複素環ジベンザゼピン、ブチロフェノン、ジフェニルブチルピペリジン及びインドロンクラスの神経弛緩薬からの化合物と併用することができる。フェノチアジンの好適な例には、クロルプロマジン、メソリダジン、チオリダジン、アセトフェナジン、フルフェナジン、ペルフェナジン及びトリフルオペラジンを含む。チオキサンテンの好適な例には、クロルプロチキセン及びチオチキセンを含む。ジベンザゼピンの例はクロザピンである。ブチロフェノンの例はハロペリドールである。ジフェニルブチルピペリジンの例はピモジドである。インドロンの例はモリンドロンである。他の神経弛緩薬には、ロキサピン、スルピリド及びリスペリドンを含む。本発明の化合物と組み合わせて使用される場合、神経弛緩薬は、医薬として許容される塩の形態、例えば、クロルプロマジン塩酸塩、ベシル酸メソリダジン、チオリダジン塩酸塩、マレイン酸アセトフェナジン、フルフェナジン塩酸塩、エナント酸フルフェナジン、デカン酸フルフェナジン、塩酸トリフルオペラジン、チオチキセン塩酸塩、デカン酸ハロペリドール、コハク酸ロキサピン及びモリンドン塩酸塩であり得ることは明らかであろう。ペルフェナジン、クロルプロチキセン、クロザピン、ハロペリドール、ピモジド及びリスペリドンは、一般に非塩形態で使用される。従って、本発明の化合物は、アセトフェナジン、アレンテモール、アリピプラゾール、アミスルプリド(amisuipride)、ベンズヘキソール、ブロモクリプチン、ビペリデン、クロルプロマジン、クロルプロチキセン、クロザピン、ジアゼパム、フェノルドパム、フルフェナジン、ハロペリドール、レボドパ、ベンセラジドとレボドパ、カルビドパとレボドパ、リスリド、ロキサピン、メソリダジン、モリンドロン、ナキサゴリド、オランザピン、ペルゴリド、ペルフェナジン、ピモジド、プラミペキソール、クエチアピン、リスペリドン、スルピリド、テトラベナジン、フリヘキシフェニジル(frihexyphenidyl)、チオリダジン、チオチキセン、トリフルオペラジン又はジプラシドンと併用することができる。 In another embodiment, the compounds of the invention can be used in combination with compounds from phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and indolon class neuroleptics. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthene include chlorprothixene and thiothixene. An example of dibenzazepine is clozapine. An example of butyrophenone is haloperidol. An example of diphenylbutylpiperidin is pimozide. An example of Indolon is Morindron. Other neuroleptics include loxapine, sulpiride and risperidone. When used in combination with the compounds of the invention, neuroleptics are pharmaceutically acceptable salt forms such as chlorpromazine hydrochloride, mesoridazine besilate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, It will be clear that fluphenazine enanthate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and morindon hydrochloride can be used. Perphenazine, chlorprotixene, clozapine, haloperidol, pimozide and risperidone are commonly used in non-salt forms. Therefore, the compounds of the present invention include acetophenazine, allentemol, alipiprazole, amisulpride, benzhexol, bromocryptin, viperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, phenoldpam, fluphenazine, haloperidol, levodopa. Levodopa, carbidopa and levodopa, lisliden, losapine, mesoridazine, morindron, nakisagolide, olanzapine, pergoride, perphenazine, pimodide, pramipexol, quetiapine, risperidone, sulpiride, tetrabenazine, frihexifenidyl It can be used in combination with gin or ziplacidone.
本発明の化合物の組み合わせの例には、疼痛治療のための薬剤、例えば非ステロイド系抗炎症剤、例えばアスピリン、ジクロフェナク、ズフルニサル(duflunisal)、フェノプロフェン、フルルビプロフェン、イブプロフェン、インドメタシン、ケトプロフェン、ケトロラク、ナプロキセン、オキサプロジン、ピロキシカム、スリンダク及びトルメチン;COX-2阻害剤、例えばセレコキシブ、ロフェコキシブ、バルデコキシブ、406381及び644784;CB-2作動薬、例えば842166及びSAB378;VR-1拮抗薬、例えばAMG517、705498、782443、PAC20030、V114380及びA425619;ブラジキニンB1受容体拮抗薬、例えばSSR240612及びNVPSAA164;ナトリウムチャンネル遮断薬及び拮抗薬、例えばVX409及びSPI860;一酸化窒素合成酵素(NOS)阻害剤(iNOS及びnNOS阻害剤など)、例えばSD6010及び274150;グリシン部位拮抗薬、例えばラコサミド;神経細胞ニコチン作動薬、例えばABT894;NMDA拮抗薬、例えばAZD4282;カリウム・チャンネル開口薬;AMPA/カイニン酸受容体拮抗薬;カルシウムチャンネル遮断薬、例えばジコノタイド及びNMED160;GABA-A受容体IO調節剤(例えば、GABA-A受容体作動薬);マトリクスメタロプロテアーゼ(MMP)阻害剤;血栓溶解剤;オピオイド系鎮痛薬、例えばコデイン、フェンタニル、ヒドロモルフォン、レボルファノール、メペリジン、メサドン、モルヒネ、オキシコドン、オキシモルフォン、ペンタゾシン、プロポキシフェン;好中球阻害因子(NIF);プラミペキソール、ロピニロール;抗コリン作用薬;アマンタジン;モノアミンオキシダーゼB15(「MAO-B」)阻害剤;5HT受容体作動薬又は拮抗薬;mGlu5拮抗薬、例えばAZD9272;α作動薬、例えばAGNXX/YY;神経細胞ニコチン作動薬、例えばABT894;NMDA受容体作動薬又は拮抗薬、例えばAZD4282;NKI拮抗薬;選択的セロトニン再取り込み阻害剤(「SSRI」)及び/又は選択的セロトニン及びノルエピネフリン再取り込み阻害剤(「SSNRI」)、例えばデュロキセチン;三環系抗鬱剤、ノルエピネフリン調節剤;リチウム;バルプロ酸塩;ガバペンチン;プレガバリン;リザトリプタン;ゾルミトリプタン;ナラトリプタン及びスマトリプタンとの組み合わせを含む。 Examples of compound combinations of the invention include agents for the treatment of pain, such as non-steroidal anti-inflammatory agents such as aspirin, diclofenac, duflunisal, phenoprofen, flurubiprofen, ibprofen, indomethacin, ketoprofen. , Ketrolac, naproxene, oxaprodin, pyroxicum, slindac and tolmethin; COX-2 inhibitors such as selecoxib, lofecoxib, valdecoxyb, 406381 and 644784; CB-2 agonists such as 842166 and SAB378; VR-1 antagonists such as AMG517, 705498, 782443, PAC20030, V114380 and A42519; brazikinin B1 receptor antagonists such as SSR240612 and NVPSAA164; sodium channel blockers and antagonists such as VX409 and SPI860; nitrogen monoxide synthase (NOS) inhibitors (iNOS and nNOS inhibition) Agents, etc.), such as SD6010 and 274150; glycine site antagonists, such as lacosamide; nerve cell nicotine agonists, such as ABT894; NMDA antagonists, such as AZD4282; potassium channel opening agents; AMPA / quinic acid receptor antagonists; calcium channels. Blockers such as diconotide and NMED160; GABA-A receptor IO regulators (eg GABA-A receptor agonists); matrix metalloprotease (MMP) inhibitors; thrombolytic agents; opioid analgesics such as codein, fentanyl , Hydromorphone, levorphanol, meperidine, mesadone, morphine, oxycodon, oxymorphone, pentazosin, propoxyphen; neutrophil inhibitor (NIF); pramipexol, ropinilol; anticholinergic agent; amantadin; monoamine oxidase B15 ("MAO" -B ") Inhibitor; 5HT receptor agonist or antagonist; mGlu5 antagonist, eg AZD9272; α agonist, eg AGNXX / YY; nerve cell nicotine agonist, eg ABT894; NMDA receptor agonist or antagonist, For example, AZD4282; NKI antagonist; selective serotonin reuptake inhibitor (“SSRI”) and / or selective serotonin and norepinephrine reuptake inhibitor (“SSNRI”), such as duroxetin; tricyclic antidepressant, norepinephrine regulator; Lithium; valproate; gabapentin; pregaba Phosphorus; Rizatriptan; Zolmitriptan; Naratriptan and sumatriptan in combination.
本発明の化合物は、睡眠の質を高め、そして睡眠障害及び睡眠の乱れを予防及び治療する上で有用な化合物、例えば鎮静剤、睡眠薬、精神安定剤、抗精神病薬、抗不安薬、抗ヒスタミン薬、ベンゾジアゼピン類、バルビツール酸塩、シクロピロロン類、オレキシン拮抗薬、α-1拮抗薬、GABA作動薬、5HT-2拮抗薬、例えば5HT-2A拮抗薬及び5HT-2A/2C拮抗薬、ヒスタミン拮抗薬、例えばヒスタミンH3拮抗薬、ヒスタミンH3逆作動薬、イミダゾピリジン、マイナートランキライザー、メラトニン作動薬及び拮抗薬、メラトニン作動薬、他のオレキシン拮抗薬、オレキシン作動薬、プロキネチシン作動薬及び拮抗薬、ピラゾロピリミジン類、T型カルシウムチャンネル拮抗薬、トリアゾロピリジン類など、例えば:アジナゾラム、アロバルビタール、アロニミド、アルプラゾラム、アミトリプチリン、アモバルビタール、アモキサピン、アルモダフィニル、APD-125、ベンタゼパム、ベンゾクタミン、ブロチゾラム、ブプロピオン、ブスプリオン、ブタバルビタール、ブタルビタール、カプロモレリン、カプリド、カルボクロラール、クロラールベタイン、抱水クロラール、クロルジアゼポキシド、クロミプラミン、クロナゼパム、クロペリドン、クロラゼパート、クロレタート(clorethate)、クロザピン、コナゼパム(conazepam)、シプラゼパム、デシプラミン、デキスクラモール、ジアゼパム、ジクロラールフェナゾン、ジバルプロエクス、ジフェンヒドラミン、ドキセピン、EMD-281014、エプリバンセリン、エスタゾラム、エスゾピクロン、エスクロリノール(ethchlorynol)、エトミダート、フェノバム、フルニトラゼパム、フルラゼパム、フルボキサミン、フルオキセチン、ホサゼパム、ガボキサドール、グルテチミド、ハラゼパム、ヒドロキシジン、イブタモレン、イミプラミン、インディプロン、リチウム、ロラゼパム、ロルメタゼパム、LY-156735、マプロチリン、MDL-100907、メクロカロン、メラトニン、メホバルビタール、メプロバメート、メタカロン、メチプリロン、ミダフルル、ミダゾラム、モダフィニル、ネファゾドン、NGD-2-73、ニソバマート、ニトラゼパム、ノルトリプチリン、オキサゼパム、パラアルデヒド、パロキセチン、ペントバルビタール、ペルラピン、ペルフェナジン、フェネルジン、フェノバルビタール、プラゼパム、プロメタジン、プロポフォール、プロトリプチリン、クアゼパム、ラメルテオン、レクラゼパム、ロレタミド、セコバルビタール、セルトラリン、スプロクロン、TAK-375、テマゼパム、チオリダジン、チアガビン、トラカゾレート、トラニルシプロマイン(tranylcypromaine)、トラゾドン、トリアゾラム、トレピパム、トリセタミド、トリクロホス、トリフルオロペラジン、トリメトジン、トリミプラミン、ウルダゼパム、ベンラファキシン、ザレプロン、ゾラゼパム、ゾピクロン、ゾルピデム及びこれらの塩、並びにそれらの組み合わせなどとの組み合わせで投与することができ、或いは本発明の化合物は、光療法又は電気刺激などの物理的方法の使用と併せて投与することができる。 The compounds of the present invention are useful compounds for improving sleep quality and preventing and treating sleep disorders and disturbed sleep, such as sedatives, sleeping pills, tranquilizers, antipsychotics, antidepressants, antihistamines. Drugs, benzodiazepines, barbiturates, cyclopyrrolones, olexin antagonists, α-1 antagonists, GABA antagonists, 5HT-2 antagonists, such as 5HT-2A antagonists and 5HT-2A / 2C antagonists, histamine. Antagonists such as histamine H3 antagonists, histamine H3 reverse agonists, imidazopyridines, minor tranquilizers, melatonin agonists and antagonists, melatonin agonists, other olexin antagonists, olexin agonists, prokineticin agonists and antagonists, pyra Zoropyrimidines, T-type calcium channel antagonists, triazolopyridines and the like, such as: azinazolam, arobarbital, aronimid, alprazolam, amitryptrin, amobarbital, amoxapine, alumodafinyl, APD-125, ventazepam, benzoctamin, brothizolam, bupropion, Busprion, butabarbital, butarbital, capromorelin, caprid, carbochloral, chloral betaine, water-holding chloral, chlordiazepoxide, chromipramine, chronazepam, cloperidone, chlorazepert, chloretate, clorethate, clozapin, konazepam (conazepam) Mole, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014, eprivanserin, estazolam, eszopicron, ethchlorynol, etmidart, phenobam, flunitrazepam, flulazepam Gavoxador, glutetimide, harazepam, hydroxydine, ibutamolen, imiplamine, indipron, lithium, lorazepam, lormetazepam, LY-156735, maplotyline, MDL-100907, mecrocaron, melatonin, mehobalbital, meprobamate, metacaron , Nefazodon, NGD-2-73, Nisobamart, Nitrazepam, Nortryptrin, Oxazepam, Paraaldehyde, Paloxetin, Pentovartal, Perlapin, Perphenazine , Phenobarbital, Prazepam, Promethazine, Propofol, Protryptrin, Quazepam, Ramelteon, Leclazepam, Loretamide, Secobarbital, Celtraline, Sprocron, TAK-375, Temazepam, Thioridazine, Thiagabin, Tracazolate , Trazodon, triazolam, trepipam, trisetamide, triclophos, trifluoroperazine, trimetidine, trimipramine, uldazepam, benrafaxin, zalepron, zorazepam, zopiclone, zolpidem and salts thereof, and combinations thereof. Alternatively, the compounds of the invention can be administered in conjunction with the use of physical methods such as phototherapy or electrical stimulation.
本発明の化合物は、単独で、又は、メマンチンのようなNMDA受容体拮抗薬と組み合わせて、若しくはドネペジルのようなアセチルコリンエステラーゼ阻害剤(AChEI)と組み合わせて、中等度ないし重度のアルツハイマー型認知症の治療に有用である。 The compounds of the invention can be used alone, in combination with NMDA receptor antagonists such as memantine, or in combination with an acetylcholinesterase inhibitor (AChEI) such as donepezil, for moderate to severe Alzheimer's disease. Useful for treatment.
本発明の化合物は、単独で、又は、ガランタミン、リバスティグミン若しくはドネペジルのいずれかと組み合わせて、軽度ないし中等度のアルツハイマー型認知症の治療に有用である。 The compounds of the present invention are useful in the treatment of mild to moderate Alzheimer's disease alone or in combination with either galantamine, rivastigmin or donepezil.
本発明の化合物は、単独で又はリバスティグミンと組み合わせて、パーキンソン病に関連する認知症の治療に有用である。 The compounds of the present invention are useful in the treatment of dementia associated with Parkinson's disease, alone or in combination with rivastigmin.
本発明の化合物は、単独で又はカルビドパ及びレボドパと組み合わせて、進行したパーキンソン病患者における運動変動の治療に有用である。 The compounds of the present invention are useful in the treatment of motor variability in advanced Parkinson's disease patients alone or in combination with carbidopa and levodopa.
患者に対して本発明の組み合わせ療法薬を投与する場合、その組み合わせる治療剤又は治療剤を含む医薬組成物若しくは組成物は、いかなる順序で投与しても良く、例えば順次、同時、一体、同時期などで投与することができる。そのような併用療法における各種活性薬剤の量は、異なる量(異なる投与量)又は同じ量(同じ投与量)であり得る。本発明の化合物及び別の治療剤は、単一の投与単位(例えば、カプセル、錠剤など)中の、固定量(投与量)で存在し得る。 When the combination therapeutic agent of the present invention is administered to a patient, the combined therapeutic agent or the pharmaceutical composition or composition containing the therapeutic agent may be administered in any order, for example, sequentially, simultaneously, integrally, and at the same time. It can be administered by such as. The amounts of the various active agents in such combination therapy can be different amounts (different doses) or the same amount (same dose). The compounds of the invention and other therapeutic agents may be present in fixed doses (dose) within a single dosing unit (eg, capsules, tablets, etc.).
本発明の化合物のα7nAChRポジティブアロステリック調節剤(PAM)活性は、当業界で公知のアッセイを用いて調べることができる。本明細書に記載のα7nAChR PAM類は、実施例で記載の自動パッチクランプ電気生理機能アッセイにおいて活性を有する。そのアッセイは、全細胞群パッチ形態でのIonFlux HTを用いて行った。Golden et al. Assay Drug Dev. Technol. (2011)9:608-619を参照する。天然α7作動薬アセチルコリンの存在下及び非存在下の両方でHEK細胞系で安定に発現されるヒトα7nAChRの機能を調節する能力について、化合物のアッセイを行った。各種濃度で一連のそのような測定を行うことで、α7nAChR PAM類の有効濃度(EC50)を求めた。Spencer et al. Assay Drug Dev. Technol. (2012)10:313-324を参照する。 The α7nAChR positive allosteric regulator (PAM) activity of the compounds of the invention can be investigated using assays known in the art. The α7nAChR PAMs described herein are active in the automated patch clamp electrophysiological function assay described in the Examples. The assay was performed with IonFlux HT in whole cell population patch form. Golden et al. Assay Drug Dev. Technol. (2011) 9: 608-619. Compound assays were performed for the ability to regulate the function of human α7nAChR, which is stably expressed in HEK cell lines both in the presence and absence of the native α7 agonist acetylcholine. By performing a series of such measurements at various concentrations, the effective concentration of α7nAChR PAMs (EC 50 ) was determined. Speaker et al. Assay Drug Dev. Technol. (2012) 10: 313-324.
一般図式
本発明の化合物は、容易に利用可能な原料、試薬及び従来の合成手順を用いて、下記の図式及び具体的実施例又はそれらの改変型に従って容易に製造することができる。これらの反応において、それ自体が当業者に公知であるがあまり詳細には言及されていない変形形態を用いることも可能である。本発明で特許請求した化合物の一般的製造手順を、下記の図式を見ることで当業者は容易に理解及び認識することができる。
General Scheme The compounds of the present invention can be readily prepared using readily available raw materials, reagents and conventional synthetic procedures according to the following schemes and specific examples or variants thereof. In these reactions, it is also possible to use variants that are known to those of skill in the art but not mentioned in great detail. Those skilled in the art can easily understand and recognize the general manufacturing procedure of the compound claimed in the present invention by looking at the following diagram.
本発明の多くの化合物が図式1に従って製造することができ、ボロン酸1.1を、パラジウム触媒条件下にブロミド1.2(アリール又はヘテロアリールであることができる)と反応させて生成物1.3を得る。ボロン酸に代えてボロン酸エステル若しくはボロン酸誘導体を、そしてブロミドに代わるものとしてクロライド、ヨージド、トリフレート若しくはトシレートを用いて同様の化学を行うことができる。多様な異なる触媒(ニッケルのような他の金属を含む)、リガンド、塩基及び溶媒をこの反応で用いることができる。次に、化合物1.3を、ニート状のクロロスルホン酸で処理することでスルホニル化し、次に、得られたスルホニルクロライドを溶媒中のアンモニア(例えば、水、1,4-ジオキサン、テトラヒドロフラン又はメタノール)溶液で処理して、スルホンアミド生成物1.4を得る。同様の化学を、ニート状の酸とは対照的にハロゲン化溶媒及びクロロスルホン酸の混合物を用いて行うことができる。1.4がエナンチオマー又はジアステレオマーの混合物である場合、その混合物をキラルクロマトグラフィーによって分離することができる。或いは、1.1及び1.2を単一のエナンチオマー又はジアステレオマーとして用いて、単一のエナンチオマー又はジアステレオマーが豊富化された1.4を得ることができる。 Many compounds of the invention can be prepared according to Scheme 1 and the product 1 is obtained by reacting boronic acid 1.1 with bromide 1.2 (which can be aryl or heteroaryl) under palladium-catalyzed conditions. Get .3. Similar chemistry can be performed using boronic acid esters or boronic acid derivatives in place of boronic acid, and chloride, iodide, triflate or tosylate as alternatives to bromide. A wide variety of different catalysts (including other metals such as nickel), ligands, bases and solvents can be used in this reaction. Compound 1.3 is then treated with a neat chlorosulfonic acid to sulfonylate the resulting sulfonyl chloride, and then the resulting sulfonyl chloride is subjected to ammonia in a solvent (eg, water, 1,4-dioxane, tetrahydrofuran or methanol). ) Treat with solution to give sulfonamide product 1.4. Similar chemistry can be performed with a mixture of halogenated solvent and chlorosulfuric acid as opposed to neat acids. If 1.4 is a mixture of enantiomers or diastereomers, the mixture can be separated by chiral chromatography. Alternatively, 1.1 and 1.2 can be used as a single enantiomer or diastereomer to obtain a single enantiomer or diastereomer-enriched 1.4.
図式1Schematic 1
本発明の具体的な化合物を図式2に記載のこの一般法を用いて製造することができ、(2-フェニルシクロプロピル)ボロン酸(2.1)を、パラジウム触媒条件下に2-ブロモピリジン2.2と反応させて生成物2.3を得る。多様な異なる触媒(ニッケルのような他の金属を含む)、リガンド、塩基及び溶媒をこの反応で用いることができる。次に、ピリジン2.3を、クロロスルホン酸で処理することでスルホニル化し、得られたスルホニルクロライドを水酸化アンモニウム水溶液と反応させて、ラセミ体のスルホンアミド生成物2.4を得る。次に、ラセミ体スルホンアミド2.4をキラルクロマトグラフィーによって分離して、個々のエナンチオマーを得ることができる。 Specific compounds of the invention can be prepared using this general method set forth in Figure 2 with (2-phenylcyclopropyl) boronic acid (2.1) in 2-bromopyridine under palladium-catalyzed conditions. React with 2.2 to give product 2.3. A wide variety of different catalysts (including other metals such as nickel), ligands, bases and solvents can be used in this reaction. The pyridine 2.3 is then treated with chlorosulfonic acid to sulfonylate and the resulting sulfonyl chloride is reacted with an aqueous ammonium hydroxide solution to give the racemic sulfonamide product 2.4. The racemic sulfonamide 2.4 can then be separated by chiral chromatography to give individual enantiomers.
図式2Diagram 2
さらに、本発明における化合物を図式3に従って製造することができ、α,β-不飽和ケトン3.1を、炭酸カリウムの存在下に高温でアミジン3.2と反応させて生成物3.3を得る。他の塩基及び溶媒をこの変換で用いることができる。さらに、スルホンアミドからのホルムアミジン基の除去が不完全である場合は、その反応の生成物をヒドラジン水和物で処理して、脱保護を完了させることができる。 Further, the compound of the present invention can be produced according to Scheme 3 and the α, β-unsaturated ketone 3.1 is reacted with amidine 3.2 at high temperature in the presence of potassium carbonate to give the product 3.3. obtain. Other bases and solvents can be used in this conversion. In addition, if the removal of formamidine groups from sulfonamides is incomplete, the product of the reaction can be treated with hydrazine hydrate to complete deprotection.
図式3Diagram 3
さらに、本発明の化合物は図式4に従って製造することができ、ボロン酸エステル4.1を、パラジウム触媒条件下にヘテロアリール4.2と反応させ、次に、ヒドラジン水和物で処理して生成物4.3を得る。ボロン酸に代えてボロン酸エステル若しくはボロン酸誘導体を、そしてブロミドに代わるものとしてクロライド、ヨージド、トリフレート若しくはトシレートを用いて、同様の化学を行うことができる。多様な異なる触媒(ニッケルのような他の金属を含む)、リガンド、塩基及び溶媒をこの反応で用いることができる。 Further, the compounds of the present invention can be prepared according to FIG. 4, and the boronic acid ester 4.1 is reacted with heteroaryl 4.2 under palladium-catalyzed conditions and then treated with hydrazine hydrate to produce the compound. Get thing 4.3. Similar chemistry can be performed using boronic acid esters or boronic acid derivatives in place of boronic acid, and chloride, iodide, triflate or tosylate as alternatives to bromide. A wide variety of different catalysts (including other metals such as nickel), ligands, bases and solvents can be used in this reaction.
図式4Schematic 4
本発明における具体的な化合物を図式5に従って、上記の一般法により製造することができ、ピナコールボロン酸エステル5.1をパラジウム触媒条件下に3-ブロモピリジン5.2と反応させ、次に、ヒドラジン水和物で処理して生成物5.3を得る。 The specific compound in the present invention can be prepared according to the above general method according to the above general method, and the pinacol boronic acid ester 5.1 is reacted with 3-bromopyridine 5.2 under palladium-catalyzed conditions, and then Treatment with hydrazine hydrate gives product 5.3.
図式5Schematic 5
本発明における6.2のような中間体は図式6に従って製造することができ、ブロミド6.1を、環境温度以下で水素化ナトリウム及びn-ブチルリチウムで処理し、次にトリイソプロピルボレートと反応させ、次にHCl水溶液で処理して、ボロン酸6.2を得る。他のアルキルリチウム塩基、ホウ素源及び酸をこの変換で用いることができる。 Intermediates such as 6.2 in the present invention can be prepared according to Scheme 6 and bromide 6.1 is treated with sodium hydride and n-butyllithium below ambient temperature and then reacted with triisopropylborate. Then, it is treated with an aqueous HCl solution to obtain 6.2 boronic acid. Other alkyllithium bases, boron sources and acids can be used in this conversion.
図式6Diagram 6
本発明における3.1のような中間体を図式7に従って製造することができ、アルデヒド7.1を、アセトン中水酸化ナトリウム水溶液で処理し、次に、得られたスチレンを、水素化ナトリウムの存在下にヨウ化トリメチルスルホキソニウムと反応させることでシクロプロパン7.2を得る。第1段階で、他の塩基を用いてその変換を行うことができ、第2段階として、シモンズ・スミス反応のような他のシクロプロパン化反応を用いて7.2のような生成物を得ることができる。次に、シクロプロパン7.2をDMF-DMAと反応させて、α,β-不飽和ケトン3.1を得る。 An intermediate such as 3.1 in the present invention can be produced according to Scheme 7, in which aldehyde 7.1 is treated with an aqueous solution of sodium hydroxide in acetone, and then the resulting styrene is treated with sodium hydride. Cyclopropane 7.2 is obtained by reacting with trimethylsulfoxonium iodide in the presence. In the first step, the conversion can be carried out using other bases, and in the second step, other cyclopropaneation reactions such as the Simmons-Smith reaction are used to obtain products such as 7.2. be able to. Next, cyclopropane 7.2 is reacted with DMF-DMA to obtain α, β-unsaturated ketone 3.1.
図式7Diagram 7
本発明における8.5のような中間体を図式8に従って製造することができる。その手順では、スルホンアミド8.1を高温でDMF-DMAで処理してアリールブロミド8.2を得ることに始まる。次に、アリールブロミド8.2を、パラジウム触媒条件下にボロン酸アルケニル8.3と反応させて、ボロン酸スチレニル8.4を得る。各種の異なる触媒(ニッケルのような他の金属を含む)、配位子、塩基及び溶媒をこの反応で用いることができる。次に、ボロン酸スチレニル8.4を酢酸パラジウムの存在下にTMSDで処理し、次に、得られたシクロプロパンをトリフ酸で処理することでボロン酸シクロプロピル8.5を得ることができる。他のパラジウム、銅又はロジウム触媒を、シクロプロパン化反応で用いることができる。 Intermediates such as 8.5 in the present invention can be produced according to Scheme 8. The procedure begins with treating sulfonamide 8.1 with DMF-DMA at elevated temperatures to give aryl bromide 8.2. Aryl bromide 8.2 is then reacted with alkenyl boronate 8.3 under palladium-catalyzed conditions to give styrenyl boronate 8.4. A variety of different catalysts (including other metals such as nickel), ligands, bases and solvents can be used in this reaction. Next, styrenyl boronate 8.4 is treated with TMSD in the presence of palladium acetate, and then the resulting cyclopropane is treated with trific acid to give cyclopropyl boronate 8.5. Other palladium, copper or rhodium catalysts can be used in the cyclopropaneation reaction.
図式8Schematic 8
さらに、本発明における中間体を図式9に従って製造することができ、ボロン酸9.1を、パラジウム触媒条件下にブロミド9.2(アリール又はヘテロアリールであり得る)と反応させてアリールクロライド9.3を得る。ボロン酸に代えてボロン酸エステル若しくはボロン酸誘導体を、そしてブロミドに代わるものとして例えばヨージド、トリフレート若しくはトシレートを用いて、同様の化学を行うことができる。多様な異なる触媒(ニッケルのような他の金属を含む)、リガンド、塩基、添加物(銅塩若しくはリチウム塩を含む)及び溶媒を、この反応で用いることができる。 Further, the intermediate in the present invention can be prepared according to Scheme 9, and boronic acid 9.1 is reacted with bromide 9.2 (which can be aryl or heteroaryl) under palladium-catalyzed conditions to make aryl chloride 9. Get 3. Similar chemistry can be performed using boronic acid esters or boronic acid derivatives in place of boronic acid and, for example, iodide, triflate or tosylate as alternatives to bromide. A wide variety of different catalysts (including other metals such as nickel), ligands, bases, additives (including copper or lithium salts) and solvents can be used in this reaction.
図式9Diagram 9
本発明における特定の中間体は、図式10に従って上記のスズキ-ミヤウラカップリング法を用いて製造することができ、3-ピリジルボロン酸10.1を、パラジウム触媒条件下にブロモピリミジン10.2と反応させて、アリールクロライド10.3を得る。 The particular intermediate in the present invention can be prepared using the Suzuki-Miyaura coupling method described above according to Scheme 10 and 3-pyridylboronic acid 10.1 with bromopyrimidine 10.2 under palladium-catalyzed conditions. To obtain aryl chloride 10.3.
図式10Schematic 10
図式11は、本発明のピリミジン系化合物の合成を示す。アミジン11.1は、当業者には公知の標準的な方法を用いて、カルボン酸1.1のような中間体から容易に製造することができる。例えば炭酸カリウム/メタノールを用いる塩基性条件下でのそのようなアミジンとケトン11.2との反応によって、所望のピリミジン11.3が得られる。異なるパターンの置換を有する各種のピリミジン系化合物は、同様の方法を用いて得ることができる。 Schematic 11 shows the synthesis of the pyrimidine compound of the present invention. Amidine 11.1 can be readily prepared from intermediates such as carboxylic acid 1.1 using standard methods known to those of skill in the art. The reaction of such amidine with the ketone 11.2 under basic conditions using, for example, potassium carbonate / methanol gives the desired pyrimidine 11.3. Various pyrimidine compounds with different patterns of substitution can be obtained using similar methods.
図式11Schematic 11
前記の反応図式における化合物及び中間体は、同様の中間体が関与する他の図式における合成中間体として用いて、別の本発明の化合物を製造することができることは明らかである。 It is clear that the compounds and intermediates in the reaction schemes described above can be used as synthetic intermediates in other schemes involving similar intermediates to produce another compound of the invention.
いくつかの例では、前記反応図式を行う順序を変えることで、反応を促進するか又は望ましくない反応生成物を回避することができる。加えて、有機合成の当業者に知られている各種保護基戦略を用いて、その反応を促進するか又は望ましくない反応生成物を回避することができる。 In some examples, the order in which the reaction schemes are performed can be changed to facilitate the reaction or avoid unwanted reaction products. In addition, various protecting group strategies known to those skilled in the art of organic synthesis can be used to facilitate the reaction or avoid unwanted reaction products.
いくつかの例では、例えば置換基を操作することで、最終生成物をさらに修飾することができる。これらの操作には、当業者には一般に知られている還元、酸化、アルキル化、アシル化及び加水分解反応を含んでよく、これらに限定されるものではない。 In some examples, the final product can be further modified, for example by manipulating substituents. These operations may include, but are not limited to, reduction, oxidation, alkylation, acylation and hydrolysis reactions commonly known to those of skill in the art.
以下の実施例は、本発明についての理解をより深めることを目的として提供されるものである。これらの実施例は、説明のみを目的とするものであって、いかなる形でも本発明を制限するものと解釈すべきではない。ラセミ混合物が得られる場合、そのエナンチオマーは、最終生成物の単離後又は好適な中間体の時点で、SFC逆相若しくは順相キラル分割条件を用いて分離し、その後に単一の異性体を個別に処理することができる。これらの重要な中間体及び実施例の合成で代替の方法を用いることも可能であることは明らかである。可能であり適切である場合、不斉法(例えば、キラル触媒作用、補助剤)を用いることができる。試薬、溶媒、温度及び他の反応条件の正確な選択は、所期の生成物の性質に依存する。 The following examples are provided for the purpose of deepening the understanding of the present invention. These examples are for illustration purposes only and should not be construed as limiting the invention in any way. When a racemic mixture is obtained, its enantiomers are separated using SFC reverse phase or normal phase chiral splitting conditions after isolation of the final product or at the time of suitable intermediates, followed by a single isomer. Can be processed individually. It is clear that alternative methods can also be used in the synthesis of these important intermediates and examples. Asymmetric methods (eg, chiral catalysis, auxiliaries) can be used where possible and appropriate. The exact choice of reagents, solvents, temperatures and other reaction conditions depends on the nature of the intended product.
本説明を通じて、下記の略称を用いている。
中間体1Intermediate 1
(トランス-2-フェニルシクロプロピル)ボロン酸
水素化ナトリウム(20.2g、505mmol)のテトラヒドロフラン(700mL)中溶液に、-70℃でトランス-(2-ブロモシクロプロピル)ベンゼン(90.0g、457mmol)を30分間かけて滴下した。n-ブチルリチウムの溶液(2.5Mヘキサン中溶液、202mL、504mmol)をゆっくり加え、反応混合物を5分間攪拌し、次にトリイソプロピルボレート(260g、1.38mol)のテトラヒドロフラン(260mL)中溶液を滴下した。反応混合物を徐々に環境温度に昇温させ、そして14時間攪拌した。HCl水溶液(2M、2L)をゆっくり加え、得られた混合物を酢酸エチルで抽出した(500mLで2回)。合わせた有機抽出液を飽和塩化ナトリウム水溶液(500mL)で洗浄し、脱水し(硫酸ナトリウム)、減圧下に濃縮した。石油エーテル(100mL)及び水(200mL)を加え、得られた混合物を濾過した。沈殿を石油エーテルで洗浄し、酢酸エチル(300mL)に溶かし、脱水し(硫酸ナトリウム)、減圧下に濃縮した。残留物を、水及びエタノールの3:1混合物から再結晶して、標題化合物を得た。MS:m/z=163.0[M+H]。
Trans- (2-bromocyclopropyl) benzene (90.0 g, 457 mmol) in a solution of (trans-2-phenylcyclopropyl) sodium hydride (20.2 g, 505 mmol) in tetrahydrofuran (700 mL) at −70 ° C. ) Was added dropwise over 30 minutes. A solution of n-butyllithium (solution in 2.5 M hexanes, 202 mL, 504 mmol) is slowly added, the reaction mixture is stirred for 5 minutes, then a solution of triisopropylborate (260 g, 1.38 mol) in tetrahydrofuran (260 mL). Dropped. The reaction mixture was gradually warmed to ambient temperature and stirred for 14 hours. Aqueous HCl (2M, 2L) was added slowly and the resulting mixture was extracted with ethyl acetate (twice at 500mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (500 mL), dehydrated (sodium sulfate) and concentrated under reduced pressure. Petroleum ether (100 mL) and water (200 mL) were added and the resulting mixture was filtered. The precipitate was washed with petroleum ether, dissolved in ethyl acetate (300 mL), dehydrated (sodium sulfate) and concentrated under reduced pressure. The residue was recrystallized from a 3: 1 mixture of water and ethanol to give the title compound. MS: m / z = 163.0 [M + H].
中間体2Intermediate 2
N-[(ジメチルアミノ)メチリデン]-4-[トランス-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)シクロプロピル]ベンゼンスルホンアミド
段階A:4-ブロモ-N-[(ジメチルアミノ)メチリデン]ベンゼンスルホンアミド
4-ブロモベンゼンスルホンアミド(5.00g、21.2mmol)のN,N-ジメチルホルムアミドジメチルアセタール(113mL)中の攪拌溶液を110℃で18時間加熱し、次に、環境温度に放冷した。得られた混合物を減圧下に濃縮して標題化合物を次の段階で使用するのに十分な純度で得た。MS:m/z=291.0[M+H]。
N-[(dimethylamino) methylidene] -4- [trans-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) cyclopropyl] benzenesulfonamide
Step A: Stirring solution of 4-bromo-N-[(dimethylamino) methylidene] benzenesulfonamide 4-bromobenzenesulfonamide (5.00 g, 21.2 mmol) in N, N-dimethylformamide dimethylacetal (113 mL). Was heated at 110 ° C. for 18 hours and then allowed to cool to ambient temperature. The resulting mixture was concentrated under reduced pressure to give the title compound with sufficient purity for use in the next step. MS: m / z = 291.0 [M + H].
段階B:N-[(ジメチルアミノ)メチリデン]-4-[(E)-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)エテニル]ベンゼンスルホンアミド
4-ブロモ-N-[(ジメチルアミノ)メチリデン]ベンゼンスルホンアミド(6.10g、21.0mmol)のトルエン(70mL)中の攪拌溶液に、環境温度でビニルボロン酸ピナコールエステル(7.11mL、41.9mmol)、ビス(トリ-tert-ブチルホスフィン)パラジウム(0)(535mg、1.05mmol)及びトリエチルアミン(6.42mL、46.1mmol)を加えた。得られた混合物を80℃で18時間加熱し、次に水(100mL)に投入し、酢酸エチルで抽出した(200mLで2回)。合わせた有機抽出液を飽和塩化ナトリウム水溶液(100mL)で洗浄し、脱水し(硫酸ナトリウム)、濾過し、減圧下に濃縮した。残留物を、酢酸エチル:ヘキサン-0:100から30:70の勾配で溶離を行うシリカゲルクロマトグラフィーによって精製して、標題化合物を得た。MS:m/z=365.3[M+H]。
Step B: N-[(dimethylamino) methylidene] -4-[(E) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) ethenyl] benzene sulfone Amide 4-bromo-N-[(dimethylamino) methylidene] benzenesulfonamide (6.10 g, 21.0 mmol) in a stirring solution in toluene (70 mL) with vinylboronic acid pinacol ester (7.11 mL, 41) at ambient temperature. .9 mmol), bis (tri-tert-butylphosphine) palladium (0) (535 mg, 1.05 mmol) and triethylamine (6.42 mL, 46.1 mmol) were added. The resulting mixture was heated at 80 ° C. for 18 hours, then poured into water (100 mL) and extracted with ethyl acetate (twice at 200 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (100 mL), dehydrated (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: hexane-0: 100 to 30:70 to give the title compound. MS: m / z = 365.3 [M + H].
段階C:N-[(ジメチルアミノ)メチリデン]-4-[トランス-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-3-(トリメチルシリル)シクロプロピル]ベンゼンスルホンアミド
N-[(ジメチルアミノ)メチリデン]-4-[(E)-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)エテニル]ベンゼンスルホンアミド(6.00g、16.5mmol)のテトラヒドロフラン(82mL)中の攪拌溶液に、環境温度で酢酸パラジウム(II)(924mg、4.12mmol)及び(トリメチルシリル)ジアゾメタン(2.0Mジエチルエーテル中溶液、24.7mL、49.4mmol)を順次加えた。反応混合物を環境温度で18時間攪拌し、次に、酢酸(12mL)を加え、得られた混合物を水(200mL)に投入し、ジクロロメタンで抽出した(200mLで3回)。合わせた有機抽出液を脱水し(硫酸ナトリウム)、濾過し、減圧下に濃縮した。残留物を、酢酸エチル:ヘキサン-10:90から60:40の勾配で溶離を行うシリカゲルクロマトグラフィーによって精製して、標題化合物を得た。MS:m/z=451.3[M+H]。
Step C: N- [(dimethylamino) methylidene] -4- [trans-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3- (trimethylsilyl) Cyclopropyl] benzenesulfonamide N-[(dimethylamino) methylidene] -4-[(E) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) etherenyl ] In a stirred solution of benzenesulfonamide (6.00 g, 16.5 mmol) in tetrahydrofuran (82 mL) at ambient temperature palladium (II) acetate (924 mg, 4.12 mmol) and (trimethylsilyl) diazomethane (2.0 M diethyl ether). Medium solution, 24.7 mL, 49.4 mmol) were added sequentially. The reaction mixture was stirred at ambient temperature for 18 hours, then acetic acid (12 mL) was added, the resulting mixture was added to water (200 mL) and extracted with dichloromethane (3 times at 200 mL). The combined organic extracts were dehydrated (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: hexane-10: 90 to 60:40 to give the title compound. MS: m / z = 451.3 [M + H].
段階D:N-[(ジメチルアミノ)メチリデン]-4-[トランス-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)シクロプロピル]ベンゼンスルホンアミド
N-[(ジメチルアミノ)メチリデン]-4-[トランス-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-3-(トリメチルシリル)シクロプロピル]ベンゼンスルホンアミド(1.25g、2.77mmol)のジクロロメタン(22mL)中の攪拌溶液に、0℃で、トリフルオロメタンスルホン酸(0.801mL、9.02mmol)を加えた。反応混合物を環境温度に昇温させ、そして2時間攪拌し、次に、飽和重炭酸ナトリウム水溶液(50mL)に投入し、ジクロロメタンで抽出した(100mLで2回)。合わせた有機抽出液を脱水し(硫酸ナトリウム)、濾過し、減圧下に濃縮した。残留物を、メタノール:ジクロロメタン-0:100から4:96の勾配で溶離を行うシリカゲルクロマトグラフィーによって精製して、標題化合物を得た。MS:m/z=379.3[M+H]。
Step D: N-[(dimethylamino) methylidene] -4- [trans-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) cyclopropyl] benzenesulfonamide N-[(dimethylamino) methylidene] -4- [trans-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3- (trimethylsilyl) cyclopropyl] Trifluoromethanesulfonic acid (0.801 mL, 9.02 mmol) was added to a stirred solution of benzenesulfonamide (1.25 g, 2.77 mmol) in dichloromethane (22 mL) at 0 ° C. The reaction mixture was warmed to ambient temperature and stirred for 2 hours, then poured into saturated aqueous sodium bicarbonate solution (50 mL) and extracted with dichloromethane (twice at 100 mL). The combined organic extracts were dehydrated (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of methanol: dichloromethane-0: 100 to 4:96 to give the title compound. MS: m / z = 379.3 [M + H].
中間体3Intermediate 3
(1R,2R)-2-(4-スルファモイルフェニル)シクロプロパンカルボン酸
段階A:エチル(1R,2R)-2-(4-スルファモイルフェニル)シクロプロパンカルボキシレート
エチルトランス-2-フェニルシクロプロパンカルボキシレート(700g、3.68mol)のクロロホルム(6リットル)中の攪拌溶液に、0℃でクロロスルホン酸(2.45リットル、36.8mol)を滴下した。得られた混合物を環境温度に昇温させ、攪拌を2時間続け、次いで反応混合物を0℃に冷却し、水(3リットル)を加えることで反応停止した。得られた混合物をジクロロメタンで抽出し(3リットルで2回)、合わせた有機抽出液を脱水し(硫酸ナトリウム)、濾過し、減圧下に濃縮した。残留物を1,4-ジオキサン(15リットル)に溶かし、水酸化アンモニウム溶液(30%、2.1リットル、18.0mol)を滴下した。得られた混合物を環境温度で30分間攪拌し、水(10リットル)で希釈した。得られた混合物を酢酸エチルで抽出し(5リットルで3回)、合わせた有機抽出液を飽和塩化ナトリウム水溶液(10リットル)で洗浄し、脱水し(硫酸ナトリウム)、濾過し、減圧下に濃縮してラセミ体の標題化合物を得た。エナンチオマーを、Chiralcel OD-Hカラムを用い、エタノール:二酸化炭素:ジエチルアミン-20:80:0.2で溶離を行うSFCによって分割した。第1の主要溶出ピークは、エチル(1S,2S)-2-(4-スルファモイルフェニル)シクロプロパンカルボキシレートであり、第2の主要溶出ピークは、標題化合物のエチル(1R,2R)-2-(4-スルファモイルフェニル)シクロプロパンカルボキシレートであった。MS:m/z=270.1[M+H]。
(1R, 2R) -2- (4-Sulfamoylphenyl) cyclopropanecarboxylic acid
Step A: Stirring of ethyl (1R, 2R) -2- (4-sulfamoylphenyl) cyclopropanecarboxylate ethyltrans-2-phenylcyclopropanecarboxylate (700 g, 3.68 mol) in chloroform (6 liters). Chlorosulfuric acid (2.45 liters, 36.8 mol) was added dropwise to the solution at 0 ° C. The resulting mixture was heated to ambient temperature, stirring was continued for 2 hours, then the reaction mixture was cooled to 0 ° C. and water (3 liters) was added to terminate the reaction. The resulting mixture was extracted with dichloromethane (twice at 3 liters), the combined organic extracts were dehydrated (sodium sulfate), filtered and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (15 liters) and an ammonium hydroxide solution (30%, 2.1 liters, 18.0 mol) was added dropwise. The resulting mixture was stirred at ambient temperature for 30 minutes and diluted with water (10 liters). The resulting mixture was extracted with ethyl acetate (3 times at 5 liters), the combined organic extracts were washed with saturated aqueous sodium chloride solution (10 liters), dehydrated (sodium sulfate), filtered and concentrated under reduced pressure. The title compound of the racemic form was obtained. Enantiomers were split by SFC elution with ethanol: carbon dioxide: diethylamine-20: 80: 0.2 using a Chiralcel OD-H column. The first major elution peak is ethyl (1S, 2S) -2- (4-sulfamoylphenyl) cyclopropanecarboxylate, and the second major elution peak is the title compound ethyl (1R, 2R)-. It was 2- (4-sulfamoylphenyl) cyclopropanecarboxylate. MS: m / z = 270.1 [M + H].
段階B:(1R,2R)-2-(4-スルファモイルフェニル)シクロプロパンカルボン酸
環境温度のエチル(1R,2R)-2-(4-スルファモイルフェニル)シクロプロパンカルボキシレート(190g、0.705mol)のテトラヒドロフラン(3リットル)及びメタノール(600mL)中の攪拌溶液に、0℃で水酸化ナトリウム水溶液(2.12M、1.00リットル、2.12mol)を滴下した。得られた混合物を環境温度で2時間攪拌し、次に減圧下に濃縮して有機溶媒を除去した。得られた混合物を、塩酸水溶液(2.0M)を加えることでpH=4に調節し、酢酸エチルで抽出し(2リットルで2回)、合わせた有機抽出液を飽和塩化ナトリウム水溶液(1リットル)で洗浄し、脱水し(硫酸ナトリウム)、濾過し、減圧下に濃縮した。残留物をジエチルエーテルからの再結晶によって精製し、標題化合物を得た。MS:m/z=242.1[M+H]。
Step B: (1R, 2R) -2- (4-sulfamoylphenyl) cyclopropanecarboxylic acid Environmental temperature ethyl (1R, 2R) -2- (4-sulfamoylphenyl) cyclopropanecarboxylate (190 g, An aqueous sodium hydroxide solution (2.12M, 1.00 liter, 2.12 mol) was added dropwise at 0 ° C. to a stirred solution of 0.705 mol) in tetrahydrofuran (3 liters) and methanol (600 mL). The resulting mixture was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure to remove the organic solvent. The obtained mixture was adjusted to pH = 4 by adding an aqueous hydrochloric acid solution (2.0 M), extracted with ethyl acetate (twice with 2 liters), and the combined organic extract was mixed with a saturated aqueous sodium chloride solution (1 liter). ) Was washed, dehydrated (sodium sulfate), filtered, and concentrated under reduced pressure. The residue was purified by recrystallization from diethyl ether to give the title compound. MS: m / z = 242.1 [M + H].
中間体4Intermediate 4
(1S,2S)-2-(4-スルファモイルフェニル)シクロプロパンカルボン酸
本質的に中間体2に記載の手順に従い、但し、エチル(1R,2R)-2-(4-スルファモイルフェニル)シクロプロパンカルボキシレートに代えてエチル(1S,2S)-2-(4-スルファモイルフェニル)シクロプロパンカルボキシレート(中間体2に記載)を用いて、標題化合物を得た。MS:m/z=242.1[M+H]。
(1S, 2S) -2- (4-Sulfamoylphenyl) cyclopropanecarboxylic acid Essentially according to the procedure described in Intermediate 2, but with ethyl (1R, 2R) -2- (4-sulfamoylphenyl). ) Ethyl (1S, 2S) -2- (4-sulfamoylphenyl) cyclopropanecarboxylate (described in Intermediate 2) was used in place of cyclopropanecarboxylate to give the title compound. MS: m / z = 242.1 [M + H].
中間体5Intermediate 5
(1R,3R)-2,2-ジメチル-3-(4-スルファモイルフェニル)シクロプロパンカルボン酸
段階A:(1R,3R)-2,2-ジメチル-3-フェニルシクロプロパンカルボン酸
トランス-2,2-ジメチル-3-フェニルシクロプロパンカルボン酸(957g、5.03mol)のエナンチオマーを、Lux-5uカラムを用い、メタノール:二酸化炭素-30:70で溶離を行うSFCによって分割した。第1の主要溶出ピークは標題化合物である(1R,3R)-2,2-ジメチル-3-フェニルシクロプロパンカルボン酸であり、第2の主要溶出ピークは(1S,3S)-2,2-ジメチル-3-フェニルシクロプロパンカルボン酸であった。MS:m/z=191.1[M+H]。
(1R, 3R) -2,2-dimethyl-3- (4-sulfamoylphenyl) cyclopropanecarboxylic acid
Step A: Lux-, an enantiomer of (1R, 3R) -2,2-dimethyl-3-phenylcyclopropanecarboxylic acid trans-2,2-dimethyl-3-phenylcyclopropanecarboxylic acid (957 g, 5.03 mol). A 5u column was used and split by SFC elution with methanol: carbon dioxide-30:70. The first major elution peak is the title compound (1R, 3R) -2,2-dimethyl-3-phenylcyclopropanecarboxylic acid, and the second major elution peak is (1S, 3S) -2,2-. It was dimethyl-3-phenylcyclopropanecarboxylic acid. MS: m / z = 191.1 [M + H].
段階B:エチル(1R,3R)-2,2-ジメチル-3-フェニルシクロプロパンカルボキシレート
(1R,3R)-2,2-ジメチル-3-フェニルシクロプロパンカルボン酸(267g、1.40mol)のエタノール(2.7リットル)中の攪拌溶液に、0℃で塩化チオニル(497g、4.21mol)を滴下した。得られた溶液を環境温度で1時間攪拌し、減圧下に濃縮した。残留物を酢酸エチル(2リットル)に溶かし、飽和重炭酸ナトリウム水溶液(1.5リットルで2回)及び飽和塩化ナトリウム水溶液(3リットル)で洗浄し、脱水し(硫酸マグネシウム)、減圧下に濃縮して標題化合物を得た。MS:m/z=219.1[M+H]。
Step B: of ethyl (1R, 3R) -2,2-dimethyl-3-phenylcyclopropanecarboxylate (1R, 3R) -2,2-dimethyl-3-phenylcyclopropanecarboxylic acid (267 g, 1.40 mol). Thionyl chloride (497 g, 4.21 mol) was added dropwise at 0 ° C. to the stirred solution in ethanol (2.7 liters). The resulting solution was stirred at ambient temperature for 1 hour and concentrated under reduced pressure. The residue is dissolved in ethyl acetate (2 liters), washed with saturated aqueous sodium bicarbonate solution (twice at 1.5 liters) and saturated aqueous sodium chloride solution (3 liters), dehydrated (magnesium sulfate), and concentrated under reduced pressure. The title compound was obtained. MS: m / z = 219.1 [M + H].
段階C:エチル(1R,3R)-2,2-ジメチル-3-(4-スルファモイルフェニル)シクロプロパンカルボキシレート
エチル(1R,3R)-2,2-ジメチル-3-フェニルシクロプロパンカルボキシレート(245g、1.12mol)のクロロホルム(2.5リットル)中の攪拌溶液に、0℃でクロロスルホン酸(1564g、13.48mol)を滴下した。得られた溶液を0℃で30分間攪拌し、環境温度に昇温させ、そして2時間攪拌した。反応混合物を0℃に冷却し、水(2リットル)を加え、得られた溶液を酢酸エチルで抽出した(3リットルで2回)。有機抽出液を合わせ、飽和塩化ナトリウム水溶液(3リットル)で洗浄し、脱水し(硫酸マグネシウム)、減圧下に濃縮した。残留物を1,4-ジオキサン(9リットル)に溶かし、5℃に冷却し、水酸化アンモニウム溶液(30%、1.75リットル、13.5mol)を加えた。得られた溶液を環境温度で30分間攪拌し、水(5リットル)で希釈し、得られた溶液を酢酸エチルで抽出した(3リットルで3回)。合わせた有機抽出液を飽和塩化ナトリウム水溶液(5リットル)で洗浄し、脱水し(硫酸マグネシウム)、減圧下に濃縮した。残留物を、酢酸エチル:石油エーテル-17:83から33:67の勾配を用いて溶離を行うシリカゲルクロマトグラフィーによって精製して、標題化合物を得た。MS:m/z=298.0[M+H]。
Step C: Ethyl (1R, 3R) -2,2-dimethyl-3- (4-sulfamoylphenyl) cyclopropanecarboxylate Ethyl (1R, 3R) -2,2-dimethyl-3-phenylcyclopropanecarboxylate Chlorosulfonic acid (1564 g, 13.48 mol) was added dropwise at 0 ° C. to a stirred solution of (245 g, 1.12 mol) in chloroform (2.5 liters). The resulting solution was stirred at 0 ° C. for 30 minutes, heated to ambient temperature and stirred for 2 hours. The reaction mixture was cooled to 0 ° C., water (2 liters) was added and the resulting solution was extracted with ethyl acetate (twice with 3 liters). The organic extracts were combined, washed with saturated aqueous sodium chloride solution (3 liters), dehydrated (magnesium sulfate), and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (9 liters), cooled to 5 ° C., and ammonium hydroxide solution (30%, 1.75 liters, 13.5 mol) was added. The resulting solution was stirred at ambient temperature for 30 minutes, diluted with water (5 liters) and the resulting solution was extracted with ethyl acetate (3 liters 3 times). The combined organic extracts were washed with saturated aqueous sodium chloride solution (5 liters), dehydrated (magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: petroleum ether-17: 83 to 33:67 to give the title compound. MS: m / z = 298.0 [M + H].
段階D:(1R,3R)-2,2-ジメチル-3-(4-スルファモイルフェニル)シクロプロパンカルボン酸
(1R,3R)-エチル2,2-ジメチル-3-(4-スルファモイルフェニル)シクロプロパンカルボキシレート(15g、50.4mmol)のテトラヒドロフラン(400mL)及びメタノール(100mL)中溶液に、環境温度で水酸化ナトリウム(1.0M、150mL、150mmol)を加えた。反応混合物を60℃に昇温させ、2.5時間攪拌した。反応混合物を0℃に冷却し、塩酸(1.00M、12.5mL、151mmol)をゆっくり加え、得られた混合物を減圧下に濃縮して、メタノール、テトラヒドロフラン及び少量の水を除去した。混合物を酢酸エチルで抽出し(200mLで3回)、合わせた有機抽出液を飽和塩化ナトリウム水溶液(150mL)で洗浄し、脱水し(硫酸ナトリウム)、濾過し、減圧下に濃縮して標題化合物を得た。MS:m/z=270.1[M+H]。
Step D: (1R, 3R) -2,2-dimethyl-3- (4-sulfamoylphenyl) cyclopropanecarboxylic acid (1R, 3R) -ethyl 2,2-dimethyl-3- (4-sulfamoyl) Sodium hydroxide (1.0 M, 150 mL, 150 mmol) was added to a solution of phenyl) cyclopropanecarboxylate (15 g, 50.4 mmol) in tetrahydrofuran (400 mL) and methanol (100 mL) at ambient temperature. The reaction mixture was heated to 60 ° C. and stirred for 2.5 hours. The reaction mixture was cooled to 0 ° C., hydrochloric acid (1.00 M, 12.5 mL, 151 mmol) was added slowly and the resulting mixture was concentrated under reduced pressure to remove methanol, tetrahydrofuran and a small amount of water. The mixture was extracted with ethyl acetate (200 mL 3 times), the combined organic extracts were washed with saturated aqueous sodium chloride solution (150 mL), dehydrated (sodium sulfate), filtered and concentrated under reduced pressure to give the title compound. Obtained. MS: m / z = 270.1 [M + H].
中間体6Intermediate 6
(1S,3S)-2,2-ジメチル-3-(4-スルファモイルフェニル)シクロプロパンカルボン酸
(1R,3R)-2,2-ジメチル-3-フェニルシクロプロパンカルボン酸に代えて(1S,3S)-2,2-ジメチル-3-フェニルシクロプロパンカルボン酸(中間体4で記載)を用いた以外は中間体4に記載の手順に実質的に従って、標題化合物を得た。MS:m/z=270.2[M+H]。
Instead of (1S, 3S) -2,2-dimethyl-3- (4-sulfamoylphenyl) cyclopropanecarboxylic acid (1R, 3R) -2,2-dimethyl-3-phenylcyclopropanecarboxylic acid (1S) , 3S) -2,2-Dimethyl-3-phenylcyclopropanecarboxylic acid (described in Intermediate 4) was used, but the procedure described in Intermediate 4 was substantially followed to give the title compound. MS: m / z = 270.2 [M + H].
中間体7Intermediate 7
(1S,3S)-2,2-ジフルオロ-3-(4-スルファモイルフェニル)シクロプロパンカルボン酸
段階A:エチル(1S,3S)-2,2-ジフルオロ-3-(4-スルファモイルフェニル)シクロプロパンカルボキシレート
クロロスルホン酸(35.5mL、530mmol)に、0℃でエチルトランス-2,2-ジフルオロ-3-フェニルシクロプロパンカルボキシレート(10.0g、44.2mmol)(Dolbier et al. J. Fluorine Chem. (2004) 125:459-469)を滴下した。反応混合物を0℃で30分間攪拌し、環境温度に昇温させ、2時間攪拌した。反応混合物を、ゆっくり攪拌した氷/水(500mL)に5分間かけてゆっくり加えた。得られた懸濁液を酢酸エチル(400mL)で希釈し、5分間攪拌した。層を分離し、水層を酢酸エチルで抽出した(400mLで2回)。合わせた有機抽出液を水(400mL)で洗浄し、脱水し(硫酸マグネシウム)、減圧下に濃縮した。残留物を1,4-ジオキサン(400mL)に溶かし、水酸化アンモニウム(30%、92mL、1.36mol)を加えた。反応混合物を環境温度で2.5時間攪拌し、減圧下に濃縮した。残留物を酢酸エチル:ヘキサン-0:100から40:60の勾配を用いて溶離を行うシリカゲルクロマトグラフィーによって精製して、ラセミ体の標題化合物を得た。そのラセミ体を、イソプロパノール:二酸化炭素:ジエチルアミン-20:80:0.1で溶離を行うChiralPak AD-Hカラムを用いるSFCによって分割した。第1の主要溶出ピークはエチル(1R,3R)-2,2-ジフルオロ-3-(4-スルファモイルフェニル)シクロプロパンカルボキシレートであり、第2の主要溶出ピークは標題化合物であるエチル(1S,3S)-2,2-ジフルオロ-3-(4-スルファモイルフェニル)シクロプロパンカルボキシレートであった。MS:m/z=306.2[M+H]。
(1S, 3S) -2,2-difluoro-3- (4-sulfamoylphenyl) cyclopropanecarboxylic acid
Step A: Ethyl trans-2, in ethyl (1S, 3S) -2,2-difluoro-3- (4-sulfamoylphenyl) cyclopropanecarboxylate chlorosulfonic acid (35.5 mL, 530 mmol) at 0 ° C. 2-Difluoro-3-phenylcyclopropanecarboxylate (10.0 g, 44.2 mmol) (Dolvier et al. J. Fluorine Chem. (2004) 125: 459-469) was added dropwise. The reaction mixture was stirred at 0 ° C. for 30 minutes, heated to environmental temperature and stirred for 2 hours. The reaction mixture was slowly added to slowly stirred ice / water (500 mL) over 5 minutes. The resulting suspension was diluted with ethyl acetate (400 mL) and stirred for 5 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (twice at 400 mL). The combined organic extracts were washed with water (400 mL), dehydrated (magnesium sulfate) and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (400 mL) and ammonium hydroxide (30%, 92 mL, 1.36 mol) was added. The reaction mixture was stirred at ambient temperature for 2.5 hours and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: hexane-0: 100 to 40:60 to give the racemic title compound. The racemate was split by SFC using a CrystalPak AD-H column elution with isopropanol: carbon dioxide: diethylamine-20: 80: 0.1. The first major elution peak is ethyl (1R, 3R) -2,2-difluoro-3- (4-sulfamoylphenyl) cyclopropanecarboxylate, and the second major elution peak is the title compound ethyl ( It was 1S, 3S) -2,2-difluoro-3- (4-sulfamoylphenyl) cyclopropanecarboxylate. MS: m / z = 306.2 [M + H].
段階B:(1S,3S)-2,2-ジフルオロ-3-(4-スルファモイルフェニル)シクロプロパンカルボン酸
エチル(1S,3S)-2,2-ジフルオロ-3-(4-スルファモイルフェニル)シクロプロパンカルボキシレート(500mg、1.64mmol)のアセトニトリル(8.2mL)中溶液に水酸化リチウム水溶液(1.0M、4.9mL、4.9mmol)を加え、反応混合物を環境温度で18時間攪拌した。反応混合物を減圧下に濃縮し、水層をHCl水溶液(1M)で酸性とした。混合物を酢酸エチルで抽出し(20mLで3回)、合わせた有機抽出液を飽和塩化ナトリウム水溶液(20mL)で洗浄し、脱水し(硫酸マグネシウム)、減圧下に濃縮して標題化合物を得た。MS:m/z=278.1[M+H]。
Step B: (1S, 3S) -2,2-difluoro-3- (4-sulfamoylphenyl) ethyl cyclopropanecarboxylate (1S, 3S) -2,2-difluoro-3- (4-sulfamoyl) Aqueous lithium hydroxide solution (1.0 M, 4.9 mL, 4.9 mmol) is added to a solution of phenyl) cyclopropanecarboxylate (500 mg, 1.64 mmol) in acetonitrile (8.2 mL), and the reaction mixture is heated to 18 at ambient temperature. Stir for hours. The reaction mixture was concentrated under reduced pressure and the aqueous layer was acidified with aqueous HCl (1M). The mixture was extracted with ethyl acetate (3 times at 20 mL), the combined organic extracts were washed with saturated aqueous sodium chloride solution (20 mL), dehydrated (magnesium sulfate) and concentrated under reduced pressure to give the title compound. MS: m / z = 278.1 [M + H].
中間体8Intermediate 8
(1R,3R)-2,2-ジフルオロ-3-(4-スルファモイルフェニル)シクロプロパンカルボン酸
エチル(1S,3S)-2,2-ジフルオロ-3-(4-スルファモイルフェニル)シクロプロパンカルボキシレートに代えてエチル(1R,3R)-2,2-ジフルオロ-3-(4-スルファモイルフェニル)シクロプロパンカルボキシレート(中間体6に記載)を用いた以外は中間体6に記載の手順に実質的に従って、標題化合物を得た。MS:m/z=278.1[M+H]。
Ethyl (1R, 3R) -2,2-difluoro-3- (4-sulfamoylphenyl) cyclopropanecarboxylate (1S, 3S) -2,2-difluoro-3- (4-sulfamoylphenyl) cyclo Described in Intermediate 6 except that ethyl (1R, 3R) -2,2-difluoro-3- (4-sulfamoylphenyl) cyclopropanecarboxylate (described in Intermediate 6) was used instead of propanecarboxylate. The title compound was obtained substantially according to the procedure of. MS: m / z = 278.1 [M + H].
中間体9Intermediate 9
(1R,3R)-3-{4-[(tert-ブトキシカルボニル)(tert-ブチル)スルファモイル]フェニル}-2,2-ジメチルシクロプロパンカルボン酸
段階A:エチル(1R,3R)-3-{4-[(tert-ブトキシカルボニル)(tert-ブチル)スルファモイル]フェニル}-2,2-ジメチルシクロプロパンカルボキシレート
エチル(1R,3R)-2,2-ジメチル-3-(4-スルファモイルフェニル)シクロプロパンカルボキシレート(中間体4で記載)(2.00g、6.73mmol)のテトラヒドロフラン(24mL)中の攪拌溶液に、環境温度でジ-tert-ブチルジカーボネート(7.34g、33.6mmol)及びDMAP(82mg、0.67mmol)を加えた。得られた混合物を環境温度で18時間、次いで50℃で7時間攪拌し、次いで環境温度まで放冷した。ジ-tert-ブチルジカーボネート(1.50g、6.87mmol)を加え、反応混合物を50℃で3時間攪拌し、環境温度まで放冷した。ジ-tert-ブチルジカーボネート(3.00g、13.7mmol)及びDMAP(82mg、0.67mmol)を加え、反応混合物を50℃で3時間攪拌し、次いで環境温度まで放冷した。得られた混合物を減圧下に濃縮し、残留物を酢酸エチル:ヘキサン-0:100から30:70の勾配を用いて溶離を行うシリカゲルクロマトグラフィーによって精製し、標題化合物を得た。MS:m/z=517.3[M+CH3CN+Na]。
(1R, 3R) -3-{4-[(tert-butoxycarbonyl) (tert-butyl) sulfamoyl] phenyl} -2,2-dimethylcyclopropanecarboxylic acid
Step A: Ethyl (1R, 3R) -3- {4-[(tert-butoxycarbonyl) (tert-butyl) sulfamoyl] phenyl} -2,2-dimethylcyclopropanecarboxylate ethyl (1R, 3R) -2, 2-Dimethyl-3- (4-sulfamoylphenyl) cyclopropanecarboxylate (described in Intermediate 4) (2.00 g, 6.73 mmol) in a stirred solution in tetrahydrofuran (24 mL) at ambient temperature. tert-Butyldicarbonate (7.34 g, 33.6 mmol) and DMAP (82 mg, 0.67 mmol) were added. The resulting mixture was stirred at ambient temperature for 18 hours and then at 50 ° C. for 7 hours and then allowed to cool to ambient temperature. Di-tert-butyl dicarbonate (1.50 g, 6.87 mmol) was added, the reaction mixture was stirred at 50 ° C. for 3 hours and allowed to cool to ambient temperature. Di-tert-butyl dicarbonate (3.00 g, 13.7 mmol) and DMAP (82 mg, 0.67 mmol) were added, the reaction mixture was stirred at 50 ° C. for 3 hours and then allowed to cool to ambient temperature. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: hexane-0: 100 to 30:70 to give the title compound. MS: m / z = 517.3 [M + CH 3 CN + Na].
段階B:(1R,3R)-3-{4-[(tert-ブトキシカルボニル)(tert-ブチル)スルファモイル]フェニル}-2,2-ジメチルシクロプロパンカルボン酸
エチル(1R,3R)-3-{4-[(tert-ブトキシカルボニル)(tert-ブチル)スルファモイル]フェニル}-2,2-ジメチルシクロプロパンカルボキシレート(2.36g、5.19mmol)のテトラヒドロフラン(15mL)及びメタノール(15mL)中の攪拌溶液に、環境温度で水酸化ナトリウム水溶液(2.0M、9.47mL、18.9mmol)を滴下した。得られた混合物を環境温度で18時間攪拌し、水(50mL)に投入した。得られた混合物を、塩酸水溶液(1.0M)を加えることでpH=4に調節し、酢酸エチルで抽出した(100mLで2回)。合わせた有機抽出液を飽和塩化ナトリウム水溶液(40mL)で洗浄し、脱水し(硫酸ナトリウム)、濾過し、減圧下に濃縮して標題化合物を得て、それをそれ以上精製せずに用いた。MS:m/z:489.2[M+CH3CN+Na]。
Step B: (1R, 3R) -3-{4-[(tert-butoxycarbonyl) (tert-butyl) sulfamoyl] phenyl} -2,2-dimethylcyclopropanecarboxylate ethyl (1R, 3R) -3-{ Stirring 4-[(tert-butoxycarbonyl) (tert-butyl) sulfamoyl] phenyl} -2,2-dimethylcyclopropanecarboxylate (2.36 g, 5.19 mmol) in tetrahydrofuran (15 mL) and methanol (15 mL). Aqueous sodium hydroxide solution (2.0 M, 9.47 mL, 18.9 mmol) was added dropwise to the solution at ambient temperature. The resulting mixture was stirred at ambient temperature for 18 hours and charged into water (50 mL). The resulting mixture was adjusted to pH = 4 by adding aqueous hydrochloric acid (1.0 M) and extracted with ethyl acetate (twice at 100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (40 mL), dehydrated (sodium sulfate), filtered and concentrated under reduced pressure to give the title compound, which was used without further purification. MS: m / z: 489.2 [M + CH 3 CN + Na].
中間体10Intermediate 10
(1S,3S)-3-{4-[(tert-ブトキシカルボニル)(tert-ブチル)スルファモイル]フェニル}-2,2-ジメチルシクロプロパンカルボン酸
エチル(1R,3R)-2,2-ジメチル-3-(4-スルファモイルフェニル)シクロプロパンカルボキシレートに代えてエチル(1S,3S)-2,2-ジメチル-3-(4-スルファモイルフェニル)シクロプロパンカルボキシレート(中間体5で記載)を用いた以外は中間体8に記載の手順に実質的に従って、標題化合物を得た。MS:m/z=489.4[M+CH3CN+Na]。
(1S, 3S) -3- {4-[(tert-butoxycarbonyl) (tert-butyl) sulfamoyl] phenyl} -2,2-dimethylcyclopropanecarboxylate ethyl (1R, 3R) -2,2-dimethyl- Ethyl (1S, 3S) -2,2-dimethyl-3- (4-sulfamoylphenyl) cyclopropanecarboxylate (described in Intermediate 5) instead of 3- (4-sulfamoylphenyl) cyclopropanecarboxylate. ) Was used, and the title compound was obtained substantially according to the procedure described in Intermediate 8. MS: m / z = 489.4 [M + CH 3 CN + Na].
中間体11Intermediate 11
2-クロロ-4-[5-(トリフルオロメチル)ピリジン-3-イル]ピリミジン
[5-(トリフルオロメチル)ピリジン-3-イル]ボロン酸(457mg、2.39mmol)のDME(8.0mL)及び水(2.0mL)中溶液に、4-ブロモ-2-クロロピリミジン(463mg、2.39mmol)及び炭酸セシウム(2.34g、7.18mmol)を加え、混合物を脱酸素した。1,1′-ビス(ジフェニルホスフィノ)フェロセン-パラジウム(II)ジクロライド、ジクロロメタン錯体(392mg、0.479mmol)を加え、反応混合物を環境温度で14時間攪拌した。反応混合物を酢酸エチル(15mL)で希釈し、水(10mL)で洗浄し、脱水し(硫酸マグネシウム)、減圧下に濃縮した。残留物を、酢酸エチル:ヘキサン-0:100から50:50の勾配で溶離を行うシリカゲルクロマトグラフィーによって精製して、標題化合物を次の段階で使用するのに十分な純度で得た。MS:m/z=260.0[M+H]。
2-Chloro-4- [5- (trifluoromethyl) pyridin-3-yl] pyrimidine [5- (trifluoromethyl) pyridin-3-yl] boronic acid (457 mg, 2.39 mmol) DME (8.0 mL) To the solution in water (2.0 mL) and 4-bromo-2-chloropyrimidine (463 mg, 2.39 mmol) and cesium carbonate (2.34 g, 7.18 mmol) were added and the mixture was deoxidized. 1,1'-Bis (diphenylphosphino) ferrocene-palladium (II) dichloride and dichloromethane complex (392 mg, 0.479 mmol) were added, and the reaction mixture was stirred at ambient temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (15 mL), washed with water (10 mL), dehydrated (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: hexane-0: 100 to 50:50 to give the title compound with sufficient purity for use in the next step. MS: m / z = 260.0 [M + H].
中間体12Intermediate 12
N-[(ジメチルアミノ)メチリデン]-4-{トランス-2-[3-(ジメチルアミノ)プロパ-2-エノイル]シクロプロピル}ベンゼンスルホンアミド
段階A:4-[(1E)-3-オキソブタ-1-エン-1-イル]ベンゼンスルホンアミド
アセトン(10.5mL)及び水(21.1mL)に溶かした4-ホルミルベンゼンスルホンアミド(2.00g、10.8mmol)の入った密閉式バイアルに、水酸化ナトリウム水溶液(5%、4.32mL、108mmol)を加えた。反応混合物を40℃に昇温させ、2日間攪拌した。反応混合物を環境温度まで冷却し、酢酸エチル(20mL)で希釈し、混合物のpHが約6となるまでHCl水溶液(1N)で処理した。層を分離し、有機層を脱水し(硫酸ナトリウム)、減圧下に濃縮し、標題化合物を次の段階で使用するのに十分な純度で得た。MS:m/z=226A[M+H]。
N-[(dimethylamino) methylidene] -4- {trans-2- [3- (dimethylamino) propa-2-enoyl] cyclopropyl} benzenesulfonamide
Step A: 4-[(1E) -3-oxobuta-1-en-1-yl] benzenesulfonamide 4-formylbenzenesulfonamide dissolved in acetone (10.5 mL) and water (21.1 mL) (2. An aqueous sodium hydroxide solution (5%, 4.32 mL, 108 mmol) was added to a closed vial containing (00 g, 10.8 mmol). The reaction mixture was heated to 40 ° C. and stirred for 2 days. The reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (20 mL) and treated with aqueous HCl (1N) until the pH of the mixture was about 6. The layers were separated, the organic layer was dehydrated (sodium sulfate) and concentrated under reduced pressure to give the title compound in sufficient purity for use in the next step. MS: m / z = 226A [M + H].
段階B:4-(トランス-2-アセチルシクロプロピル)-N-[(ジメチルアミノ)メチリデン]ベンゼンスルホンアミド
ヨウ化トリメチルスルホキソニウム(2.56g、11.6mmol)のDMSO(48.4mL)中溶液に水素化ナトリウム(0.852g、21.3mmol)を加え、反応混合物を5分間攪拌した。4-[(1E)-3-オキソブタ-1-エン-1-イル]ベンゼンスルホンアミド(2.18g、9.68mmol)を少量ずつ加え、反応混合物を14時間攪拌した。反応混合物を酢酸エチル(100mL)及び水(100mL)で希釈し、層を分離した。水層を酢酸エチルで抽出し(100mLで7回)、合わせた有機抽出液を飽和塩化ナトリウム水溶液(100mL)で洗浄し、脱水し(硫酸ナトリウム)、減圧下に濃縮した。残留物を酢酸エチル:エタノール:ヘキサン-0:0:100から75:25:0の勾配で溶離を行うシリカゲルクロマトグラフィーによって精製して、標題化合物を得た。MS:m/z=240.1[M+H]。
Step B: In DMSO (48.4 mL) of 4- (trans-2-acetylcyclopropyl) -N-[(dimethylamino) methylidene] benzenesulfonamide trimethylsulfoxonium iodide (2.56 g, 11.6 mmol). Sodium hydride (0.852 g, 21.3 mmol) was added to the solution and the reaction mixture was stirred for 5 minutes. 4-[(1E) -3-oxobuta-1-en-1-yl] benzenesulfonamide (2.18 g, 9.68 mmol) was added little by little, and the reaction mixture was stirred for 14 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and water (100 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (7 times at 100 mL), the combined organic extracts were washed with saturated aqueous sodium chloride solution (100 mL), dehydrated (sodium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: ethanol: hexane-0: 0: 100 to 75:25: 0 to give the title compound. MS: m / z = 240.1 [M + H].
段階C:N-[(ジメチルアミノ)メチリデン]-4-{トランス-2-[3-(ジメチルアミノ)プロパ-2-エノイル]シクロプロピル}ベンゼンスルホンアミド
4-(トランス-2-アセチルシクロプロピル)-N-[(ジメチルアミノ)メチリデン]ベンゼンスルホンアミド(553mg、2.31mmol)の入った密閉式バイアルに、DMF-DMA(6.19mL、46.2mmol)を加えた。反応混合物を110℃に昇温させ、14時間攪拌した。反応混合物を環境温度まで冷却し、ジクロロメタン(15mL)で希釈し、水で洗浄し(10mLで3回)、脱水し(硫酸ナトリウム)、減圧下に濃縮して、標題化合物を次の段階で使用するのに十分な純度で得た。MS:m/z=350.2[M+H]。
Step C: N-[(dimethylamino) methylidene] -4- {trans-2- [3- (dimethylamino) propa-2-enoyl] cyclopropyl} benzenesulfonamide 4- (trans-2-acetylcyclopropyl) DMF-DMA (6.19 mL, 46.2 mmol) was added to a closed vial containing -N-[(dimethylamino) methylidene] benzenesulfonamide (553 mg, 2.31 mmol). The reaction mixture was heated to 110 ° C. and stirred for 14 hours. The reaction mixture is cooled to ambient temperature, diluted with dichloromethane (15 mL), washed with water (3 times at 10 mL), dehydrated (sodium sulfate), concentrated under reduced pressure and the title compound is used in the next step. Obtained with sufficient purity to do. MS: m / z = 350.2 [M + H].
中間体13Intermediate 13
(1R,3R)-2,2-ジメチル-3-(4-スルファモイルフェニル)シクロプロパンカルボキシイミドアミド
段階A:(1R,3R)-2,2-ジメチル-3-(4-スルファモイルフェニル)シクロプロパンカルボキサミド
(1R,3R)-2,2-ジメチル-3-(4-スルファモイルフェニル)シクロプロパンカルボン酸(中間体5)(850mg、3.16mmol)のテトラヒドロフラン(10mL)中の攪拌溶液に、1,1′-カルボニルジイミダゾール(614mg、3.79mmol)を加え、得られた混合物を環境温度で1時間攪拌した。水酸化アンモニウム水溶液(28%溶液、8.8mL、130mmol)を加え、反応混合物を環境温度で12時間攪拌した。混合物を減圧下に濃縮してテトラヒドロフランを除去し、残留混合物を、1M塩酸水溶液を加えることでpH=3に調節した。水層を酢酸エチルで抽出し(10mLで3回)、合わせた有機抽出液を飽和炭酸カリウム水溶液で洗浄し(10mLで2回)、脱水し(硫酸ナトリウム)、濾過し、溶媒を減圧下に留去して、標題化合物を次の段階で使用するのに十分な純度で得た。MS:m/z=269.1[M+H]。
(1R, 3R) -2,2-dimethyl-3- (4-sulfamoylphenyl) cyclopropanecarboxyimideamide
Step A: (1R, 3R) -2,2-dimethyl-3- (4-sulfamoylphenyl) cyclopropanecarboxamide (1R, 3R) -2,2-dimethyl-3- (4-sulfamoylphenyl) To a stirred solution of cyclopropanecarboxylic acid (intermediate 5) (850 mg, 3.16 mmol) in tetrahydrofuran (10 mL) was added 1,1'-carbonyldiimidazole (614 mg, 3.79 mmol) and the resulting mixture was added. The mixture was stirred at ambient temperature for 1 hour. Aqueous ammonium hydroxide solution (28% solution, 8.8 mL, 130 mmol) was added and the reaction mixture was stirred at ambient temperature for 12 hours. The mixture was concentrated under reduced pressure to remove tetrahydrofuran and the residual mixture was adjusted to pH = 3 by adding 1M aqueous hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate (3 times at 10 mL), the combined organic extracts were washed with saturated aqueous potassium carbonate solution (2 times at 10 mL), dehydrated (sodium sulfate), filtered, and the solvent was reduced under reduced pressure. Distillate to give the title compound in sufficient purity for use in the next step. MS: m / z = 269.1 [M + H].
段階B:4-[(1R,3R)-3-シアノ-2,2-ジメチルシクロプロピル]-N-[(ジメチルアミノ)メチリデン]ベンゼンスルホンアミド
(1R,2R)-2-(4-スルファモイルフェニル)シクロプロパンカルボキサミド(500mg、1.86mmol)のN,N-ジメチルホルムアミド(8mL)中の攪拌溶液に、環境温度で塩化チオニル(3.3g、27mmol)を滴下し、得られた溶液を環境温度で1時間攪拌した。反応混合物を水(10mL)で希釈し、酢酸エチルで抽出した(10mLで3回)。合わせた有機抽出液を飽和塩化ナトリウム水溶液(25mL)で洗浄し、脱水し(硫酸ナトリウム)、減圧下に濃縮した。残留物を、酢酸エチルで溶離を行うシリカゲルクロマトグラフィーによって精製して、標題化合物を得た。MS:m/z=306.1[M+H]。
Step B: 4-[(1R, 3R) -3-cyano-2,2-dimethylcyclopropyl] -N-[(dimethylamino) methylidene] benzenesulfonamide (1R, 2R) -2- (4-sulfa) Thionyl chloride (3.3 g, 27 mmol) was added dropwise to a stirred solution of moylphenyl) cyclopropanecarboxamide (500 mg, 1.86 mmol) in N, N-dimethylformamide (8 mL) at ambient temperature, and the obtained solution was added. The mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 times at 10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution (25 mL), dehydrated (sodium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate to give the title compound. MS: m / z = 306.1 [M + H].
段階C:エチル(1R,3R)-3-(4-{[(ジメチルアミノ)メチリデン]スルファモイル}フェニル)-2,2-ジメチルシクロプロパンカルボキシイミドエート
4-[(1R,3R)-3-シアノ-2,2-ジメチルシクロプロピル]-N-[(ジメチルアミノ)メチリデン]ベンゼンスルホンアミド(180mg、0.59mmol)のエタノール(10mL)中溶液を、0℃で塩化水素(気体)で飽和させ、得られた混合物を環境温度で4時間攪拌した。反応混合物を減圧下に濃縮し、標題化合物を次の段階で使用するのに十分な純度で得た。MS:m/z=352.1[M+H]。
Step C: Ethyl (1R, 3R) -3- (4-{[(dimethylamino) methylidene] sulfamoyl} phenyl) -2,2-dimethylcyclopropanecarboxyimideate 4-[(1R, 3R) -3-cyano -2,2-Dimethylcyclopropyl] -N-[(dimethylamino) methylidene] A solution of benzenesulfonamide (180 mg, 0.59 mmol) in ethanol (10 mL) was saturated with hydrogen chloride (gas) at 0 ° C. The resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give the title compound with sufficient purity for use in the next step. MS: m / z = 352.1 [M + H].
段階D:(1R,3R)-2,2-ジメチル-3-(4-スルファモイルフェニル)シクロプロパンカルボキシイミドアミド
エチル(1R,3R)-3-(4-{[(ジメチルアミノ)メチリデン]スルファモイル}フェニル)-2,2-ジメチルシクロプロパンカルボキシイミドエート(200mg、0.57mmol)及びエタノール(5mL)の混合物に、0℃で飽和アンモニア/メタノール溶液(5mL)を加えた。反応混合物を50℃で12時間攪拌し、減圧下に濃縮し、標題化合物を次の段階で使用するのに十分な純度で得た。MS:m/z=268.0[M+H]。
Step D: (1R, 3R) -2,2-dimethyl-3- (4-sulfamoylphenyl) cyclopropanecarboxyimideamideethyl (1R, 3R) -3- (4-{[(dimethylamino) methylidene] Saturated ammonia / methanol solution (5 mL) was added to a mixture of sulfamoyl} phenyl) -2,2-dimethylcyclopropanecarboxyimideate (200 mg, 0.57 mmol) and ethanol (5 mL) at 0 ° C. The reaction mixture was stirred at 50 ° C. for 12 hours and concentrated under reduced pressure to give the title compound with sufficient purity for use in the next step. MS: m / z = 268.0 [M + H].
中間体14Intermediate 14
3-(ジメチルアミノ)-1-[5-(トリフルオロメチル)ピリジン-3-イル]プロパ-2-エン-1-オン
段階A:3-(1-エトキシエテニル)-5-(トリフルオロメチル)ピリジン
3-ブロモ-5-(トリフルオロメチル)ピリジン(500mg、2.21mmol)のN,N-ジメチルホルムアミド(8mL)中溶液に、ビス(トリフェニルホスフィン)パラジウム(II)ジクロライド(15.5mg、0.022mmol)及びトリブチル(1-エトキシビニル)スズ(959mg、2.66mmol)を環境温度で加えた。反応混合物を100℃で2時間攪拌し、環境温度まで放冷し、飽和フッ化カリウム水溶液(10mL)を加えた。得られた混合物を濾過し、濾液を酢酸エチル(30mL)で希釈し、有機層を飽和炭酸水素ナトリウム水溶液(10mLで2回)、次に飽和塩化ナトリウム水溶液(10mLで2回)で洗浄し、脱水し(硫酸ナトリウム)、濾過し、溶媒を減圧下に留去して、標題化合物を次の段階で使用するのに十分な純度で得た。MS:m/z=217.8[M+H]。
3- (dimethylamino) -1- [5- (trifluoromethyl) pyridin-3-yl] propa-2-ene-1-one
Step A: N, N-dimethylformamide (8 mL) of 3- (1-ethoxyethenyl) -5- (trifluoromethyl) pyridine 3-bromo-5- (trifluoromethyl) pyridine (500 mg, 2.21 mmol) To the medium solution was added bis (triphenylphosphine) palladium (II) dichloride (15.5 mg, 0.022 mmol) and tributyl (1-ethoxyvinyl) tin (959 mg, 2.66 mmol) at ambient temperature. The reaction mixture was stirred at 100 ° C. for 2 hours, allowed to cool to ambient temperature, and saturated aqueous potassium fluoride solution (10 mL) was added. The resulting mixture was filtered, the filtrate diluted with ethyl acetate (30 mL) and the organic layer washed with saturated aqueous sodium hydrogen carbonate solution (twice with 10 mL) and then with saturated aqueous sodium chloride solution (twice with 10 mL). It was dehydrated (sodium sulfate), filtered and the solvent was evaporated under reduced pressure to give the title compound in sufficient purity for use in the next step. MS: m / z = 217.8 [M + H].
段階B:1-[5-(トリフルオロメチル)ピリジン-3-イル]エタノン
3-(1-エトキシエテニル)-5-(トリフルオロメチル)ピリジン(450mg、2.07mmol)のテトラヒドロフラン(8mL)中の攪拌溶液に、環境温度で2M塩酸水溶液(5mL、10mmol)を加え、得られた溶液を環境温度で12時間攪拌した。反応混合物を水(10mL)で希釈し、酢酸エチルで抽出した(10mLで3回)。合わせた有機抽出液を脱水し(硫酸ナトリウム)、濾過し、減圧下に濃縮した。残留物を酢酸エチル:石油エーテル-1:5で溶離を行うシリカゲルクロマトグラフィーによって精製して、標題化合物を得た。MS:m/z=190.0[M+H]。
Step B: 1- [5- (trifluoromethyl) pyridin-3-yl] ethanone 3- (1-ethoxyethenyl) -5- (trifluoromethyl) pyridine (450 mg, 2.07 mmol) in hydrochloric acid (8 mL) A 2M aqueous hydrochloric acid solution (5 mL, 10 mmol) was added to the stirred solution inside, and the obtained solution was stirred at the ambient temperature for 12 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 times at 10 mL). The combined organic extracts were dehydrated (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate: petroleum ether-1: 5 to give the title compound. MS: m / z = 190.0 [M + H].
段階C:3-(ジメチルアミノ)-1-[5-(トリフルオロメチル)ピリジン-3-イル]プロパ-2-エン-1-オン
1-[5-(トリフルオロメチル)ピリジン-3-イル]エタノン(150mg、0.79mmol)及びtert-ブトキシビス(ジメチルアミノ)メタン(138mg、0.79mmol)の混合物を110℃で12時間攪拌した。反応混合物を環境温度まで放冷し、減圧下に濃縮し、標題化合物を次の段階で使用するのに十分な純度で得た。MS:m/z=245.1[M+H]。
Step C: 3- (dimethylamino) -1- [5- (trifluoromethyl) pyridin-3-yl] propa-2-ene- 1-one 1- [5- (trifluoromethyl) pyridin-3-yl] ] A mixture of etanone (150 mg, 0.79 mmol) and tert-butoxybis (dimethylamino) methane (138 mg, 0.79 mmol) was stirred at 110 ° C. for 12 hours. The reaction mixture was allowed to cool to ambient temperature and concentrated under reduced pressure to give the title compound with sufficient purity for use in the next step. MS: m / z = 245.1 [M + H].
中間体15Intermediate 15
(1R,3R)-2.2-ジフルオロ-3-(4-スルファモイルフェニル)シクロプロパンカルボキシイミドアミド
(1R,3R)-2,2-ジメチル-3-(4-スルファモイルフェニル)シクロプロパンカルボン酸に代えて(1R,3R)-2,2-ジフルオロ-3-(4-スルファモイルフェニル)シクロプロパンカルボン酸(中間体8)を用いた以外は中間体13に記載の手順に実質的に従って、標題化合物を得た。MS:m/z=276A[M+H]。
(1R, 3R) -2.2-difluoro-3- (4-sulfamoylphenyl) cyclopropanecarboxyimideamide (1R, 3R) -2,2-dimethyl-3- (4-sulfamoylphenyl) cyclo The procedure according to Intermediate 13 is described except that (1R, 3R) -2,2-difluoro-3- (4-sulfamoylphenyl) cyclopropanecarboxylic acid (intermediate 8) is used instead of propanecarboxylic acid. Substantially according to the title compound was obtained. MS: m / z = 276A [M + H].
中間体16Intermediate 16
3-(ジメチルアミノ)-1-(3-フルオロフェニル)プロパ-2-エン-1-オン
1-[5-(トリフルオロメチル)ピリジン-3-イル]エタノンに代えて3-フルオロアセトフェノンを用いた以外は中間体14に記載の手順に実質的に従って、標題化合物を得た。MS:m/z=194.1[M+H]。
3- (Dimethylamino) -1- (3-Fluorophenyl) propa-2-ene- 1-one 1- [5- (trifluoromethyl) pyridin-3-yl] 3-fluoroacetophenone is used instead of etanone. Substantially according to the procedure described in Intermediate 14, the title compound was obtained. MS: m / z = 194.1 [M + H].
下記の表にある中間体を、当業者に公知の修正を加え、同様の変換の結果として記載若しくは製造されるように、上記の中間体と同様にして製造した。必要な原料は、本明細書に記載されていたか、市販されていたか、文献で公知であったか又は当業者によって容易に合成された。一部の経路では、直接保護基戦略を用いた。 The intermediates listed in the table below were made in the same manner as the above intermediates, with modifications known to those of skill in the art, as described or manufactured as a result of similar conversions. The required raw materials were described herein, were commercially available, were known in the literature, or were readily synthesized by one of ordinary skill in the art. Some routes used a direct protecting group strategy.
表INT-ATable INT-A
実施例1Example 1
4-{トランス-2-[6-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド、エナンチオマーB
段階A:2-(トランス-2-フェニルシクロプロピル)-6-(プロパン-2-イル)ピリジン
(トランス-フェニルシクロプロピル)ボロン酸(中間体1)(211mg、1.30mmol)のトルエン(3.3mL)中溶液に、2-ブロモ-6-イソプロピルピリジン(137mg、0.685mmol)及び三塩基性リン酸カリウム(436mg、2.05mmol)を加え、反応混合物を窒素によって脱酸素した。酢酸パラジウム(II)(30.7mg、0.137mmol)、ジ(1-アダマンチル)-n-ブチルホスフィン(98mg、0.27mmol)及び水(0.2mL)を加え、反応混合物を窒素で脱酸素し、密閉し、100℃に昇温させ、4時間攪拌した。反応混合物を減圧下に濃縮し、残留物を酢酸エチル:ヘキサン-0:100から50:50の勾配で溶離を行うシリカゲルクロマトグラフィーによって精製し、標題化合物を得た。MS:m/z=238.2[M+H]。
4- {Trans-2- [6- (Propane-2-yl) Pyridine-2-yl] Cyclopropyl} Benzene Sulfonamide, Enantiomer B
Step A: 2- (Trans-2-phenylcyclopropyl) -6- (Propane-2-yl) Pyridine (Trans-Phenylcyclopropyl) Boronic Acid (Intermediate 1) (211 mg, 1.30 mmol) in toluene (3) To the solution in (3 mL), 2-bromo-6-isopropylpyridine (137 mg, 0.685 mmol) and tribasic potassium phosphate (436 mg, 2.05 mmol) were added, and the reaction mixture was deoxidized with nitrogen. Palladium acetate (II) (30.7 mg, 0.137 mmol), di (1-adamantyl) -n-butylphosphine (98 mg, 0.27 mmol) and water (0.2 mL) were added and the reaction mixture was deoxidized with nitrogen. The mixture was sealed, heated to 100 ° C., and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: hexane-0: 100 to 50:50 to give the title compound. MS: m / z = 238.2 [M + H].
段階B:4-{トランス-2-[6-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド、エナンチオマーB
トランス-2-(2-フェニルシクロプロピル)-6-(プロパン-2-イル)ピリジン(145mg、0.611mmol)の入ったフラスコにクロロスルホン酸(1.00mL、14.9mmol)を加え、反応混合物を30分間攪拌した。反応混合物を氷水(15mL)に滴下し、混合物をデカンテートした。残留物を1,4-ジオキサン(2mL)に溶かし、得られた溶液に水酸化アンモニウム(15M、0.50mL、7.6mmol)を加えた。反応混合物を30分間攪拌し、次に水(10mL)で希釈した。反応混合物を酢酸エチルで抽出し(15mLで2回)、合わせた有機抽出液を飽和塩化ナトリウム水溶液(10mL)で洗浄し、脱水し(硫酸マグネシウム)、減圧下に濃縮した。残留物を、酢酸エチル:エタノール:ヘキサン-3:1:96から57:19:24の勾配で溶離を行うシリカゲルクロマトグラフィーによって精製し、標題化合物を得た。そのラセミ体を、メタノール:二酸化炭素:イソプロピルアミン-35:65:0.25で溶離を行うChiralPak AD-Hカラムを用いるSFCによって分割した。第1の溶出主要ピークはトランス-4-{2-[6-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド、エナンチオマーAであり、第2の溶出主要ピークはトランス-4-{2-[6-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド、エナンチオマーB、標題化合物であった。MS:m/z=317.2[M+H]。1H NMR(500MHz、DMSO-d6):δ7.71(d、J=8.1Hz、2H);7.58(t、J=7.7Hz、1H);7.37(d、J=8.2Hz、2H);7.27(s、2H);7.15(d、J=7.6Hz、1H);7.05(d、J=7.7Hz、1H);2.92-2.97(m、1H);2.42-2.48(m、2H);1.74(dt、J=8.9、4.8Hz、1H);1.50-1.54(m、1H);1.23(d、J=1.7Hz、3H);1.22(d、J=1.8Hz、3H)。
Step B: 4- {trans-2- [6- (propane-2-yl) pyridin-2-yl] cyclopropyl} benzenesulfonamide, enantiomer B
Chlorosulfuric acid (1.00 mL, 14.9 mmol) is added to a flask containing trans-2- (2-phenylcyclopropyl) -6- (propane-2-yl) pyridine (145 mg, 0.611 mmol), and the reaction is carried out. The mixture was stirred for 30 minutes. The reaction mixture was added dropwise to ice water (15 mL) and the mixture was decantated. The residue was dissolved in 1,4-dioxane (2 mL) and ammonium hydroxide (15 M, 0.50 mL, 7.6 mmol) was added to the resulting solution. The reaction mixture was stirred for 30 minutes and then diluted with water (10 mL). The reaction mixture was extracted with ethyl acetate (twice at 15 mL), the combined organic extracts were washed with saturated aqueous sodium chloride solution (10 mL), dehydrated (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: ethanol: hexane-3: 1: 96 to 57:19:24 to give the title compound. The racemate was split by SFC using a CrystalPak AD-H column elution with methanol: carbon dioxide: isopropylamine-35: 65: 0.25. The first major elution peak is trans-4- {2- [6- (propane-2-yl) pyridin-2-yl] cyclopropyl} benzenesulfonamide, enantiomer A, and the second major elution peak is trans. -4- {2- [6- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide, enantiomer B, the title compound. MS: m / z = 317.2 [M + H]. 1 1 H NMR (500 MHz, DMSO-d 6 ): δ7.71 (d, J = 8.1 Hz, 2H); 7.58 (t, J = 7.7 Hz, 1H); 7.37 (d, J = 8.2Hz, 2H); 7.27 (s, 2H); 7.15 (d, J = 7.6Hz, 1H); 7.05 (d, J = 7.7Hz, 1H); 2.92- 2.97 (m, 1H); 2.42-2.48 (m, 2H); 1.74 (dt, J = 8.9, 4.8Hz, 1H); 1.50-1.54 (m) , 1H); 1.23 (d, J = 1.7Hz, 3H); 1.22 (d, J = 1.8Hz, 3H).
実施例2Example 2
4-{トランス-2-[2-(モルホリン-4-イル)ピリミジン-4-イル]シクロプロピル}ベンゼンスルホンアミド
N-[(ジメチルアミノ)メチリデン]-4-{トランス-2-[3-(ジメチルアミノ)プロパ-2-エノイル]シクロプロピル}ベンゼンスルホンアミド(中間体12)(30mg、0.086mmol)のエタノール(1.1mL)中溶液に、炭酸カリウム(23.7mg、0.172mmol)及びモルホリン-4-カルボキシイミドアミド(16.7mg、0.129mmol)を加えた。反応混合物を80℃に昇温させ、14時間攪拌した。反応混合物を環境温度まで冷却し、窒素気流下に濃縮し、得られた残留物を、アセトニトリル:水:トリフルオロ酢酸-10:90:0.1から40:60:0.1の勾配で溶離を行う分取HPLCによって精製し、標題化合物を得た。MS:m/z=360.1[M+H]。1H NMR(500MHz、DMSO-d6):δ8.20(d、J=5.0Hz、1H);7.72(d、J=8.1Hz、2H);7.37(d、J=8.2Hz、2H);7.28(s、2H);6.69(d、J=5.0Hz、1H);3.66-3.68(brm、8H);2.33(brs、2H);1.77(brs、1H);1.58(brs、1H)。
4- {Trans-2- [2- (morpholin-4-yl) pyrimidin-4-yl] cyclopropyl} benzenesulfonamide N-[(dimethylamino) methylidene] -4- {trans-2- [3-( Dimethylamino) propa-2-enoyl] cyclopropyl} benzenesulfonamide (intermediate 12) (30 mg, 0.086 mmol) in ethanol (1.1 mL) in ethanol (23.7 mg, 0.172 mmol) and potassium carbonate (23.7 mg, 0.172 mmol). Morphorin-4-carboxyimideamide (16.7 mg, 0.129 mmol) was added. The reaction mixture was heated to 80 ° C. and stirred for 14 hours. The reaction mixture was cooled to ambient temperature, concentrated under a nitrogen stream and the resulting residue was eluted with a gradient of acetonitrile: water: trifluoroacetic acid-10: 90: 0.1 to 40: 60: 0.1. Purification was performed by preparative HPLC to give the title compound. MS: m / z = 360.1 [M + H]. 1 1 H NMR (500 MHz, DMSO-d 6 ): δ8.20 (d, J = 5.0 Hz, 1H); 7.72 (d, J = 8.1 Hz, 2H); 7.37 (d, J = 8.2Hz, 2H); 7.28 (s, 2H); 6.69 (d, J = 5.0Hz, 1H); 3.66-3.68 (brm, 8H); 2.33 (brs, brs, 2H); 1.77 (brs, 1H); 1.58 (brs, 1H).
実施例3Example 3
4-[トランス-2-(6-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド、エナンチオマーB
段階A:2-シクロペンチル-6-(トランス-2-フェニルシクロプロピル)ピリジン
(トランス-2-フェニルシクロプロピル)ボロン酸(中間体1)(681mg、4.20mmol)のトルエン(10.5mL)及び水(0.6mL)の混合液中の溶液に、2-ブロモ-6-シクロペンチルピリジン(500mg、2.21mmol)及び三塩基性リン酸カリウム(1.41g、6.63mmol)を加え、反応混合物を窒素で脱酸素した。酢酸パラジウム(II)(99mg、0.44mmol)及びジ(1-アダマンチル)-n-ブチルホスフィン(317mg、0.885mmol)を加え、反応混合物を110℃に昇温させ、4時間攪拌した。反応混合物を酢酸エチル(20mL)で希釈し、水(10mL)及び飽和塩化ナトリウム水溶液(10mL)で洗浄し、脱水し(硫酸マグネシウム)、減圧下に濃縮した。残留物を、酢酸エチル:ヘキサン-5:95から100:0の勾配で溶離を行うシリカゲルクロマトグラフィーによって精製し、標題化合物を得た。MS:m/z=264.3[M+H]。
4- [Trans-2- (6-cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide, enantiomer B
Step A: 2-cyclopentyl-6- (trans-2-phenylcyclopropyl) pyridine (trans-2-phenylcyclopropyl) boronic acid (intermediate 1) (681 mg, 4.20 mmol) in toluene (10.5 mL) and To the solution in a mixed solution of water (0.6 mL), 2-bromo-6-cyclopentylpyridine (500 mg, 2.21 mmol) and potassium tribasic phosphate (1.41 g, 6.63 mmol) are added, and the reaction mixture is added. Was deoxidized with nitrogen. Palladium (II) acetate (99 mg, 0.44 mmol) and di (1-adamantyl) -n-butylphosphine (317 mg, 0.885 mmol) were added, the reaction mixture was heated to 110 ° C. and stirred for 4 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL), dehydrated (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: hexane-5: 95 to 100: 0 to give the title compound. MS: m / z = 264.3 [M + H].
段階B:4-[トランス-2-(6-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド、エナンチオマーB
2-シクロペンチル-6-(トランス-2-フェニルシクロプロピル)ピリジン(324mg、1.23mmol)の入ったフラスコに、クロロスルホン酸(2.00mL、29.9mmol)を加え、反応混合物を30分間攪拌した。反応混合物を氷水(20mL)に滴下し、混合物をデカンテートした。残留物を1,4-ジオキサン(3mL)に溶かし、得られた溶液に水酸化アンモニウム(15M、1.50mL、22.7mmol)を加えた。反応混合物を30分間攪拌し、水(15mL)で希釈した。反応混合物を酢酸エチルで抽出し(20mLで2回)、合わせた有機抽出液を飽和塩化ナトリウム水溶液(15mL)で洗浄し、脱水し(硫酸マグネシウム)、減圧下に濃縮した。残留物を、酢酸エチル:エタノール:ヘキサン-3:1:96から57:19:24の勾配で溶離を行うシリカゲルクロマトグラフィーによって精製し、標題化合物を得た。そのラセミ体を、メタノール:イソプロパノール:二酸化炭素:イソプロピルアミン-25:25:50:0.25で溶離を行うChiralPak AD-Hカラムを用いるSFCによって分割した。第1の溶出主要ピークは4-[トランス-2-(6-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド、エナンチオマーAであり、第2の溶出主要ピークは4-[トランス-2-(6-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド、エナンチオマーB、標題化合物であった。MS:m/z=343.2[M+H]。1H NMR(500MHz、DMSO-d6):δ7.71(d、J=8.2Hz、2H);7.55(t、J=1.6Hz、1H);7.36(d、J=8.2Hz、2H);7.27(s、2H);7.14(d、J=7.6Hz、1H);7.04(d、J=7.7Hz、1H);3.08-3.14(m、1H);2.41-2.48(m、2H);1.93-1.97(m、2H);1.70-1.76(m、5H);1.63-1.67(m、2H);1.50-1.54(m、1H)。
Step B: 4- [trans-2- (6-cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide, enantiomer B
Chlorosulfuric acid (2.00 mL, 29.9 mmol) was added to a flask containing 2-cyclopentyl-6- (trans-2-phenylcyclopropyl) pyridine (324 mg, 1.23 mmol), and the reaction mixture was stirred for 30 minutes. did. The reaction mixture was added dropwise to ice water (20 mL) and the mixture was decantated. The residue was dissolved in 1,4-dioxane (3 mL) and ammonium hydroxide (15 M, 1.50 mL, 22.7 mmol) was added to the resulting solution. The reaction mixture was stirred for 30 minutes and diluted with water (15 mL). The reaction mixture was extracted with ethyl acetate (twice at 20 mL), the combined organic extracts were washed with saturated aqueous sodium chloride solution (15 mL), dehydrated (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: ethanol: hexane-3: 1: 96 to 57:19:24 to give the title compound. The racemate was split by SFC using a CrystalPak AD-H column elution with methanol: isopropanol: carbon dioxide: isopropylamine-25: 25: 50: 0.25. The first major elution peak is 4- [trans-2- (6-cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide, enantiomer A, and the second major elution peak is 4- [trans-2-yl). (6-Cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide, enantiomer B, the title compound. MS: m / z = 343.2 [M + H]. 1 1 H NMR (500 MHz, DMSO-d 6 ): δ7.71 (d, J = 8.2 Hz, 2H); 7.55 (t, J = 1.6 Hz, 1H); 7.36 (d, J = 8.2Hz, 2H); 7.27 (s, 2H); 7.14 (d, J = 7.6Hz, 1H); 7.04 (d, J = 7.7Hz, 1H); 3.08- 3.14 (m, 1H); 2.41-2.48 (m, 2H); 1.93-1.97 (m, 2H); 1.70-1.76 (m, 5H); 1. 63-1.67 (m, 2H); 1.50-1.54 (m, 1H).
実施例4Example 4
4-[トランス-2-(5-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド、エナンチオマーB
段階A:5-シクロペンチル-2-(トランス-2-フェニルシクロプロピル)ピリジン
(トランス-2-フェニルシクロプロピル)ボロン酸(中間体1)(681mg、4.20mmol)のトルエン(10.5mL)及び水(0.6mL)の混合液中の溶液に、2-ブロモ-6-シクロペンチルピリジン(500mg、2.21mmol)及び三塩基性リン酸カリウム(1.41g、6.63mmol)を加え、反応混合物を窒素で脱酸素した。酢酸パラジウム(II)(99mg、0.44mmol)及びジ(1-アダマンチル)-n-ブチルホスフィン(317mg、0.885mmol)を加え、反応混合物を110℃に昇温させ、4時間攪拌した。反応混合物を酢酸エチル(20mL)で希釈し、水(10mL)及び飽和塩化ナトリウム水溶液(10mL)で洗浄し、脱水し(硫酸マグネシウム)、減圧下に濃縮した。残留物を、酢酸エチル:ヘキサン-5:95から100:0の勾配で溶離を行うシリカゲルクロマトグラフィーによって精製し、標題化合物を得た。MS:m/z=264.3[M+H]。
4- [Trans-2- (5-cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide, enantiomer B
Step A: 5-cyclopentyl-2- (trans-2-phenylcyclopropyl) pyridine (trans-2-phenylcyclopropyl) boronic acid (intermediate 1) (681 mg, 4.20 mmol) in toluene (10.5 mL) and To the solution in a mixed solution of water (0.6 mL), 2-bromo-6-cyclopentylpyridine (500 mg, 2.21 mmol) and potassium tribasic phosphate (1.41 g, 6.63 mmol) are added, and the reaction mixture is added. Was deoxidized with nitrogen. Palladium (II) acetate (99 mg, 0.44 mmol) and di (1-adamantyl) -n-butylphosphine (317 mg, 0.885 mmol) were added, the reaction mixture was heated to 110 ° C. and stirred for 4 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL), dehydrated (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: hexane-5: 95 to 100: 0 to give the title compound. MS: m / z = 264.3 [M + H].
段階B:4-[トランス-2-(5-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド、エナンチオマーB
5-シクロペンチル-2-(トランス-2-フェニルシクロプロピル)ピリジン(391mg、1.49mmol)の入ったフラスコに、クロロスルホン酸(2.00mL、29.9mmol)を加え、反応混合物を30分間攪拌した。反応混合物を氷水(20mL)に滴下し、混合物をデカンテートした。残留物を1,4-ジオキサン(3mL)に溶かし、得られた溶液に水酸化アンモニウム(15M、1.50mL、22.7mmol)を加えた。反応混合物を30分間攪拌し、水(15mL)で希釈した。反応混合物を酢酸エチルで抽出し(20mLで2回)、合わせた有機抽出液を飽和塩化ナトリウム水溶液(15mL)で洗浄し、脱水し(硫酸マグネシウム)、減圧下に濃縮した。残留物を、酢酸エチル:エタノール:ヘキサン-3:1:96から57:19:24の勾配で溶離を行うシリカゲルクロマトグラフィーによって精製し、標題化合物を得た。そのラセミ体を、エタノール:二酸化炭素:イソプロピルアミン-55:45:0.25で溶離を行うChiralPak AD-Hカラムを用いるSFCによって分割した。第1の溶出主要ピークは4-[トランス-2-(5-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド、エナンチオマーAであり、第2の溶出主要ピークは4-[トランス-2-(5-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド、エナンチオマーB、標題化合物であった。MS:m/z=343.2[M+H]。1H NMR(500MHz、DMSO-d6):δ8.36(d、J=2.3Hz、1H);7.71(d、J=8.1Hz、2H);7.55(dd、J=8.0、2.4Hz、1H);7.36(d、J=8.2Hz、2H);7.29(d、J=8.2Hz、1H);7.27(s、2H);2.91-2.98(m、1H);2.41-2.48(m、2H);2.01(brs、2H);1.74-1.80(m、2H);1.68-1.72(m、1H);1.65(m、2H);1.50-1.54(m、3H)。
Step B: 4- [trans-2- (5-cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide, enantiomer B
Chlorosulfuric acid (2.00 mL, 29.9 mmol) is added to a flask containing 5-cyclopentyl-2- (trans-2-phenylcyclopropyl) pyridine (391 mg, 1.49 mmol), and the reaction mixture is stirred for 30 minutes. did. The reaction mixture was added dropwise to ice water (20 mL) and the mixture was decantated. The residue was dissolved in 1,4-dioxane (3 mL) and ammonium hydroxide (15 M, 1.50 mL, 22.7 mmol) was added to the resulting solution. The reaction mixture was stirred for 30 minutes and diluted with water (15 mL). The reaction mixture was extracted with ethyl acetate (twice at 20 mL), the combined organic extracts were washed with saturated aqueous sodium chloride solution (15 mL), dehydrated (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: ethanol: hexane-3: 1: 96 to 57:19:24 to give the title compound. The racemate was split by SFC using a CrystalPak AD-H column elution with ethanol: carbon dioxide: isopropylamine-55: 45: 0.25. The first major elution peak is 4- [trans-2- (5-cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide, enantiomer A, and the second major elution peak is 4- [trans-2-yl). (5-Cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide, enantiomer B, the title compound. MS: m / z = 343.2 [M + H]. 1 1 H NMR (500 MHz, DMSO-d 6 ): δ8.36 (d, J = 2.3 Hz, 1H); 7.71 (d, J = 8.1 Hz, 2H); 7.55 (dd, J = 8.0, 2.4Hz, 1H); 7.36 (d, J = 8.2Hz, 2H); 7.29 (d, J = 8.2Hz, 1H); 7.27 (s, 2H); 2.91-2.98 (m, 1H); 2.41-2.48 (m, 2H); 2.01 (brs, 2H); 1.74-1.80 (m, 2H); 1. 68-1.72 (m, 1H); 1.65 (m, 2H); 1.50-1.54 (m, 3H).
実施例5Example 5
4-{トランス-2-[4-(プロパン-2-イル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド、エナンチオマーB
段階A:2-(トランス-2-フェニルシクロプロピル)-4-(プロパン-2-イル)ピリミジン
(トランス-2-フェニルシクロプロピル)ボロン酸(中間体1)(1.53g、9.45mmol)のトルエン(8.0mL)及び水(0.4mL)の混合液中の溶液に、2-ブロモ-4-イソプロピルピリミジン(1.0g、4.97mmol)及び三塩基性リン酸カリウム(3.17g、14.9mmol)を加え、反応混合物を窒素で脱酸素した。酢酸パラジウム(II)(223mg、0.995mmol)及びジ(1-アダマンチル)-n-ブチルホスフィン(713mg、1.99mmol)を加え、反応混合物を100℃に昇温させ、14時間攪拌した。反応混合物を酢酸エチル(20mL)で希釈し、水(10mL)及び飽和塩化ナトリウム水溶液(10mL)で洗浄し、脱水し(硫酸マグネシウム)、減圧下に濃縮した。残留物を、酢酸エチル:ヘキサン-0:100から50:50の勾配で溶離を行うシリカゲルクロマトグラフィーによって精製し、標題化合物を得た。MS:m/z=239.1[M+H]。
4- {Trans-2- [4- (Propane-2-yl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide, enantiomer B
Step A: 2- (trans-2-phenylcyclopropyl) -4- (propane-2-yl) pyrimidin (trans-2-phenylcyclopropyl) boronic acid (intermediate 1) (1.53 g, 9.45 mmol) 2-bromo-4-isopropylpyrimidine (1.0 g, 4.97 mmol) and potassium tribasic phosphate (3.17 g) in a solution of toluene (8.0 mL) and water (0.4 mL). , 14.9 mmol) was added and the reaction mixture was deoxidized with nitrogen. Palladium acetate (II) (223 mg, 0.995 mmol) and di (1-adamantyl) -n-butylphosphine (713 mg, 1.99 mmol) were added, the reaction mixture was heated to 100 ° C. and stirred for 14 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL), dehydrated (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: hexane-0: 100 to 50:50 to give the title compound. MS: m / z = 239.1 [M + H].
段階B:4-{トランス-2-[4-(プロパン-2-イル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド、エナンチオマーB
クロロスルホン酸(8.00mL、119mmol)の入ったフラスコに、0℃で2-(トランス-2-フェニルシクロプロピル)-4-(プロパン-2-イル)ピリミジン(890mg、3.73mmol)を滴下し、反応混合物を30分間攪拌した。反応混合物を環境温度まで昇温させ、1時間攪拌した。反応混合物を氷水(20mL)に滴下し、混合物をデカンテーションした。残留物を1,4-ジオキサン(8mL)に溶かし、得られた溶液に水酸化アンモニウム(15M、4.00mL、60.4mmol)を加えた。反応混合物を30分間攪拌し、酢酸エチル(25mL)で希釈した。層を分離し、水層を酢酸エチルで抽出した(30mLで2回)。合わせた有機抽出液を水(20mL)及び飽和塩化ナトリウム水溶液(20mL)で洗浄し、脱水し(硫酸マグネシウム)、減圧下に濃縮した。残留物を、酢酸エチル:エタノール:ヘキサン-3:1:96から38:12:50の勾配で溶離を行うシリカゲルクロマトグラフィーによって精製し、標題化合物を得た。そのラセミ体を、エタノール:二酸化炭素:イソプロピルアミン-50:50:0.25で溶離を行うChiralPak AD-Hカラムを用いるSFCによって分割した。第1の溶出主要ピークは4-{トランス-2-[4-(プロパン-2-イル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド、エナンチオマーAであり、第2の溶出主要ピークは4-{トランス-2-[4-(プロパン-2-イル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド、エナンチオマーB、標題化合物であった。MS:m/z=318.2[M+H]。1H NMR(500MHz、DMSO-d6):δ8.56(d、J=5.2Hz、1H);7.72(d、J=8.2Hz、2H);7.40(d、J=8.2Hz、2H);7.29(s、2H);7.21(d、J=5.2Hz、1H);2.90-2.97(m、1H);2.57-2.61(m、1H);2.51-2.54(m、1H);1.75-1.79(m、1H);1.61(ddd、J=8.6、6.1、4.1Hz、1H);1.23(d、J=1.9Hz、3H);1.22(d、J=1.9Hz、3H)。
Stage B: 4- {trans-2- [4- (propane-2-yl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide, enantiomer B
2- (Trans-2-phenylcyclopropyl) -4- (Propane-2-yl) pyrimidin (890 mg, 3.73 mmol) was added dropwise at 0 ° C. to a flask containing chlorosulfonic acid (8.00 mL, 119 mmol). The reaction mixture was stirred for 30 minutes. The reaction mixture was heated to the ambient temperature and stirred for 1 hour. The reaction mixture was added dropwise to ice water (20 mL) and the mixture was decanted. The residue was dissolved in 1,4-dioxane (8 mL) and ammonium hydroxide (15 M, 4.00 mL, 60.4 mmol) was added to the resulting solution. The reaction mixture was stirred for 30 minutes and diluted with ethyl acetate (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (twice at 30 mL). The combined organic extracts were washed with water (20 mL) and saturated aqueous sodium chloride solution (20 mL), dehydrated (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: ethanol: hexane-3: 1: 96 to 38:12:50 to give the title compound. The racemate was split by SFC using a CrystalPak AD-H column elution with ethanol: carbon dioxide: isopropylamine-50: 50: 0.25. The first major elution peak is 4- {trans-2- [4- (propane-2-yl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide, enantiomer A, and the second major elution peak is 4. -{Trans-2- [4- (Propane-2-yl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide, enantiomer B, the title compound. MS: m / z = 318.2 [M + H]. 1 1 H NMR (500 MHz, DMSO-d 6 ): δ8.56 (d, J = 5.2 Hz, 1H); 7.72 (d, J = 8.2 Hz, 2H); 7.40 (d, J = 8.2Hz, 2H); 7.29 (s, 2H); 7.21 (d, J = 5.2Hz, 1H); 2.90-2.97 (m, 1H); 2.57-2. 61 (m, 1H); 2.51-2.54 (m, 1H); 1.75-1.79 (m, 1H); 1.61 (ddd, J = 8.6, 6.1, 4) .1Hz, 1H); 1.23 (d, J = 1.9Hz, 3H); 1.22 (d, J = 1.9Hz, 3H).
実施例6Example 6
4-{トランス-2-[6-(ピロリジン-1-イル)ピリジン-3-イル]シクロプロピル}ベンゼンスルホンアミド
N-[(ジメチルアミノ)メチリデン]-4-[トランス-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)シクロプロピル]ベンゼンスルホンアミド(中間体2)(30mg、0.079mmol)のトルエン(0.79mL)中溶液に、5-ブロモ-2-(ピロリジン-1-イル)ピリジン(32mg、0.12mmol)、クロロ[(ジ(1-アダマンチル)-n-ブチルホスフィン)-2-(2-アミノビフェニル)]パラジウム(II)(5.3mg、0.0079mmol)及び三塩基性リン酸カリウム水溶液(1M、0.238mL、0.238mmol)をその順で加えた。反応混合物を100℃に昇温させ、そして18時間攪拌した。反応混合物を酢酸エチル(3mL)で希釈し、セライトの入ったSPEカートリッジで濾過し、濾液を減圧下に濃縮した。残留物をヒドラジン水和物の溶液(37%水/エタノール中溶液、1.5mL、17.6mmol)で処理し、1.5時間攪拌した。反応混合物を減圧下に濃縮し、得られた残留物をアセトニトリル:水:トリフルオロ酢酸-5:95:0.1から35:65:0.1の勾配で溶離を行う分取HPLCによって精製し、標題化合物を得た。MS:m/z=344.1[M+H]。1H NMR(500MHz、DMSO-d6):δ7.86(s、1H);7.78(d、J=9.3Hz、1H);7.73(d、J=8.0Hz、2H);7.35(d、J=8.0Hz、2H);7.29(s、2H);7.04(d、J=9.2Hz、1H);3.50(brs、4H);2.34(m、2H);2.02(brs、4H);1.57(m、2H)。
4- {Trans-2- [6- (pyrrolidin-1-yl) pyridin-3-yl] cyclopropyl} benzenesulfonamide N-[(dimethylamino) methylidene] -4- [trans-2- (4,4) , 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) cyclopropyl] benzenesulfonamide (intermediate 2) (30 mg, 0.079 mmol) in a solution in toluene (0.79 mL), 5 -Bromo-2- (pyrrolidin-1-yl) pyridine (32 mg, 0.12 mmol), chloro [(di (1-adamantyl) -n-butylphosphine) -2- (2-aminobiphenyl)] palladium (II) (5.3 mg, 0.0079 mmol) and aqueous tribasic potassium phosphate (1 M, 0.238 mL, 0.238 mmol) were added in that order. The reaction mixture was heated to 100 ° C. and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (3 mL), filtered through an SPE cartridge containing Celite, and the filtrate was concentrated under reduced pressure. The residue was treated with a solution of hydrazine hydrate (37% water / ethanol solution, 1.5 mL, 17.6 mmol) and stirred for 1.5 hours. The reaction mixture is concentrated under reduced pressure and the resulting residue is purified by preparative HPLC elution with a gradient of acetonitrile: water: trifluoroacetic acid-5: 95: 0.1 to 35: 65: 0.1. , The title compound was obtained. MS: m / z = 344.1 [M + H]. 1 1 H NMR (500 MHz, DMSO-d 6 ): δ7.86 (s, 1H); 7.78 (d, J = 9.3 Hz, 1H); 7.73 (d, J = 8.0 Hz, 2H) 7.35 (d, J = 8.0Hz, 2H); 7.29 (s, 2H); 7.04 (d, J = 9.2Hz, 1H); 3.50 (brs, 4H); 2 .34 (m, 2H); 2.02 (brs, 4H); 1.57 (m, 2H).
実施例7Example 7
4-{トランス-2-[3-(5-メチル-1,2,4-オキサジアゾール-3-イル)フェニル]シクロプロピル}ベンゼンスルホンアミド
N-[(ジメチルアミノ)メチリデン]-4-[トランス-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)シクロプロピル]ベンゼンスルホンアミド(中間体2)(30mg、0.079mmol)のトルエン(0.79mL)中溶液に、3-(3-ブロモフェニル)-5-メチル-1,2,4-オキサジアゾール(33mg、0.12mmol)、クロロ[(ジ(1-アダマンチル)-n-ブチルホスフィン)-2-(2-アミノビフェニル)]パラジウム(II)(5.3mg、0.0079mmol)及び三塩基性リン酸カリウム水溶液(1M、0.238mL、0.238mmol)をその順で加えた。反応混合物を100℃に昇温させ、そして18時間攪拌した。反応混合物を酢酸エチル(3mL)で希釈し、セライトの入ったSPEカートリッジで濾過し、濾液を減圧下に濃縮した。残留物をヒドラジン水和物の溶液(37%水/エタノール中溶液、1.5mL、17.6mmol)で処理し、1.5時間攪拌した。反応混合物を減圧下に濃縮し、得られた残留物をアセトニトリル:水:トリフルオロ酢酸-5:95:0.1から55:45:0.1の勾配で溶離を行う分取HPLCによって精製し、標題化合物を得た。MS:m/z=356.2[M+H]。1H NMR(500MHz、DMSO-d6):δ7.81(d、J=9.0Hz、2H);7.73(d、J=8.0Hz、2H);7.49(t、J=7.8Hz、1H);7.40(t、J=8.5Hz、3H);7.28(s、2H);2.67(s、3H);2.46(s、1H);2.39(s、1H);1.62(s、2H)。
4- {Trans-2- [3- (5-methyl-1,2,4-oxadiazole-3-yl) phenyl] cyclopropyl} benzenesulfonamide N-[(dimethylamino) methylidene] -4- [ Trans-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) cyclopropyl] benzenesulfonamide (intermediate 2) (30 mg, 0.079 mmol) in toluene (0) In a solution in (.79 mL), 3- (3-bromophenyl) -5-methyl-1,2,4-oxadiazole (33 mg, 0.12 mmol), chloro [(di (1-adamantyl) -n-butyl) Hosphin) -2- (2-aminobiphenyl)] palladium (II) (5.3 mg, 0.0079 mmol) and aqueous tribasic potassium phosphate solution (1M, 0.238 mL, 0.238 mmol) were added in that order. .. The reaction mixture was warmed to 100 ° C. and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (3 mL), filtered through an SPE cartridge containing Celite, and the filtrate was concentrated under reduced pressure. The residue was treated with a solution of hydrazine hydrate (37% water / ethanol solution, 1.5 mL, 17.6 mmol) and stirred for 1.5 hours. The reaction mixture is concentrated under reduced pressure and the resulting residue is purified by preparative HPLC elution with a gradient of acetonitrile: water: trifluoroacetic acid-5: 95: 0.1 to 55: 45: 0.1. , The title compound was obtained. MS: m / z = 356.2 [M + H]. 1 1 H NMR (500 MHz, DMSO-d 6 ): δ7.81 (d, J = 9.0 Hz, 2H); 7.73 (d, J = 8.0 Hz, 2H); 7.49 (t, J = 7.8Hz, 1H); 7.40 (t, J = 8.5Hz, 3H); 7.28 (s, 2H); 2.67 (s, 3H); 2.46 (s, 1H); 2 .39 (s, 1H); 1.62 (s, 2H).
実施例8Example 8
4-{トランス-2-[2-(プロパン-2-イル)ピリジン-4-イル]シクロプロピル}ベンゼンスルホンアミド、エナンチオマーB
段階A:4-(トランス-2-フェニルシクロプロピル)-2-(プロパン-2-イル)ピリジン
(トランス-2-フェニルシクロプロピル)ボロン酸(中間体1)(769mg、4.75mmol)のトルエン(9.5mL)及び水(0.5mL)の混合液中の溶液に、2-ブロモ-4-イソプロピルピリミジン(500mg、2.50mmol)及び三塩基性リン酸カリウム(1.59g、7.50mmol)を加え、反応混合物を窒素で脱酸素した。酢酸パラジウム(II)(112mg、0.500mmol)及びジ(1-アダマンチル)-n-ブチルホスフィン(358mg、1.00mmol)を加え、反応混合物を100℃に昇温させ、そして14時間攪拌した。反応混合物を酢酸エチル(20mL)で希釈し、水(10mL)及び飽和塩化ナトリウム水溶液(10mL)で洗浄し、脱水し(硫酸マグネシウム)、減圧下に濃縮した。残留物を、酢酸エチル:ヘキサン-0:100から50:50の勾配で溶離を行うシリカゲルクロマトグラフィーによって精製し、標題化合物を得た。MS:m/z=238.0[M+H]。
4- {Trans-2- [2- (Propane-2-yl) Pyridine-4-yl] Cyclopropyl} Benzene Sulfonamide, Enantiomer B
Step A: Toluene of 4- (trans-2-phenylcyclopropyl) -2- (propane-2-yl) pyridine (trans-2-phenylcyclopropyl) boronic acid (intermediate 1) (769 mg, 4.75 mmol) 2-Bromo-4-isopropylpyrimidine (500 mg, 2.50 mmol) and potassium tribasic phosphate (1.59 g, 7.50 mmol) in a solution in a mixture of (9.5 mL) and water (0.5 mL). ) Was added, and the reaction mixture was deoxidized with nitrogen. Palladium (II) acetate (112 mg, 0.500 mmol) and di (1-adamantyl) -n-butylphosphine (358 mg, 1.00 mmol) were added, the reaction mixture was warmed to 100 ° C. and stirred for 14 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL), dehydrated (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: hexane-0: 100 to 50:50 to give the title compound. MS: m / z = 238.0 [M + H].
段階B:4-{トランス-2-[2-(プロパン-2-イル)ピリジン-4-イル]シクロプロピル}ベンゼンスルホンアミド、エナンチオマーB
4-(トランス-2-フェニルシクロプロピル)-2-(プロパン-2-イル)ピリジン(472mg、1.99mmol)のジクロロメタン(4.0mL)中溶液に、0℃でクロロスルホン酸(2.00mL、29.9mmol)を滴下し、反応混合物を30分間攪拌した。反応混合物を環境温度に昇温させ、そして30分間攪拌した。反応混合物を0℃まで冷却し、氷水(15mL)に滴下し、層を分離した。水層をジクロロメタンで抽出し(15mLで3回)、合わせた有機抽出液を減圧下に濃縮した。残留物を1,4-ジオキサン(3.0mL)に溶かし、得られた溶液に水酸化アンモニウム(15M、1.00mL、15.1mmol)を加えた。反応混合物を14時間攪拌し、酢酸エチル(25mL)で希釈した。層を分離し、水層を酢酸エチルで抽出した(30mLで2回)。合わせた有機抽出液を水(20mL)及び飽和塩化ナトリウム水溶液(20mL)で洗浄し、脱水し(硫酸マグネシウム)、減圧下に濃縮した。残留物を酢酸エチル:エタノール:ヘキサン-3:1:96から38:12:50の勾配で溶離を行うシリカゲルクロマトグラフィーによって精製し、標題化合物を得た。そのラセミ体を、メタノール:二酸化炭素:イソプロピルアミン-30:70:0.25で溶離を行うChiralPak AD-Hカラムを用いるSFCによって分割した。第1の溶出主要ピークは4-{トランス-2-[2-(プロパン-2-イル)ピリジン-4-イル]シクロプロピル}ベンゼンスルホンアミド、エナンチオマーAであり、第2の溶出主要ピークは4-{トランス-2-[2-(プロパン-2-イル)ピリジン-4-イル]シクロプロピル}ベンゼンスルホンアミド、エナンチオマーB、標題化合物であった。MS:m/z=317.2[M+H]。1H NMR(500MHz、DMSO-d6):δ8.34(d、J=5.2Hz、1H);7.72(d、J=8.2Hz、2H);7.37(d、J=8.2Hz、2H);7.28(s、2H);7.10(s、1H);6.98-6.99(m、1H);2.93-2.98(m、1H);2.40-2.43(m、1H);2.27-2.31(m、1H);1.61-1.67(m、2H);1.22(s、3H);1.21(s、3H)。
Step B: 4- {trans-2- [2- (propane-2-yl) pyridin-4-yl] cyclopropyl} benzenesulfonamide, enantiomer B
4- (Trans-2-phenylcyclopropyl) -2- (Propane-2-yl) Pyridine (472 mg, 1.99 mmol) in a solution in dichloromethane (4.0 mL) at 0 ° C. with chlorosulfonic acid (2.00 mL). , 29.9 mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes. The reaction mixture was warmed to ambient temperature and stirred for 30 minutes. The reaction mixture was cooled to 0 ° C. and added dropwise to ice water (15 mL) to separate the layers. The aqueous layer was extracted with dichloromethane (3 times at 15 mL) and the combined organic extracts were concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (3.0 mL) and ammonium hydroxide (15 M, 1.00 mL, 15.1 mmol) was added to the resulting solution. The reaction mixture was stirred for 14 hours and diluted with ethyl acetate (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (twice at 30 mL). The combined organic extracts were washed with water (20 mL) and saturated aqueous sodium chloride solution (20 mL), dehydrated (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: ethanol: hexane-3: 1: 96 to 38:12:50 to give the title compound. The racemate was split by SFC using a CrystalPak AD-H column elution with methanol: carbon dioxide: isopropylamine-30: 70: 0.25. The first major elution peak is 4- {trans-2- [2- (propane-2-yl) pyridin-4-yl] cyclopropyl} benzenesulfonamide, enantiomer A, and the second major elution peak is 4. -{Trans-2- [2- (Propane-2-yl) Pyridine-4-yl] cyclopropyl} benzenesulfonamide, enantiomer B, the title compound. MS: m / z = 317.2 [M + H]. 1 1 H NMR (500 MHz, DMSO-d 6 ): δ8.34 (d, J = 5.2 Hz, 1H); 7.72 (d, J = 8.2 Hz, 2H); 7.37 (d, J = 8.2Hz, 2H); 7.28 (s, 2H); 7.10 (s, 1H); 6.98-6.99 (m, 1H); 2.93-2.98 (m, 1H) 2.40-2.43 (m, 1H); 2.22-2.31 (m, 1H); 1.61-1.67 (m, 2H); 1.22 (s, 3H); 1 .21 (s, 3H).
実施例9Example 9
4-[(1R,3R)-2,2-ジメチル-3-{4-[5-(トリフルオロメチル)ピリジン-3-イル]ピリミジン-2-イル}シクロプロピル]ベンゼンスルホンアミド
3-(ジメチルアミノ)-1-[5-(トリフルオロメチル)ピリジン-3-イル]プロパ-2-エン-1-オン(中間体14)(15mg、0.06mmol)のメタノール(1mL)中溶液に、環境温度で(1R,3R)-2,2-ジメチル-3-(4-スルファモイルフェニル)シクロプロパンカルボキシイミドアミド(中間体13)(33mg、0.12mmol)及び炭酸カリウム(8.5mg、0.06mmol)を加えた。攪拌反応混合物を60℃で12時間加熱し、環境温度に放冷し、次いでアセトニトリル:水:水酸化アンモニウム-35:65:0.05から65:35:0.05の勾配で溶離を行う分取HPLCによって精製し、生成物含有分画を減圧下に濃縮して標題化合物を得た。MS:m/z=449.0[M+H]。1H NMR(400MHz、CD3OD):δ9.61(s、1H);9.05(s、1H);8.83-8.90(m、2H);7.98(d、J=5.3Hz、1H);7.87(d、J=8.3Hz、2H);7.51(d、J=7.9Hz、2H);3.27-3.29(m、1H);2.91(d、J=6.1Hz、1H);1.34(s、3H);1.07(s、3H)。
4-[(1R, 3R) -2,2-dimethyl-3-{4- [5- (trifluoromethyl) pyridin-3-yl] pyrimidin-2-yl} cyclopropyl] benzenesulfonamide 3- (dimethyl) Amino) -1- [5- (trifluoromethyl) Pyridine-3-yl] propa-2-ene-1-one (intermediate 14) (15 mg, 0.06 mmol) in a solution in methanol (1 mL), environment. At temperature (1R, 3R) -2,2-dimethyl-3- (4-sulfamoylphenyl) cyclopropanecarboxyimideamide (intermediate 13) (33 mg, 0.12 mmol) and potassium carbonate (8.5 mg, 0) .06 mmol) was added. The stirring reaction mixture is heated at 60 ° C. for 12 hours, allowed to cool to ambient temperature, and then eluted with a gradient of acetonitrile: water: ammonium hydroxide-35: 65: 0.05 to 65: 35: 0.05. Purification was performed by taking HPLC, and the product-containing fraction was concentrated under reduced pressure to give the title compound. MS: m / z = 449.0 [M + H]. 1 1 H NMR (400 MHz, CD 3 OD): δ9.61 (s, 1H); 9.05 (s, 1H); 8.83-8.90 (m, 2H); 7.98 (d, J = 5.3Hz, 1H); 7.87 (d, J = 8.3Hz, 2H); 7.51 (d, J = 7.9Hz, 2H); 3.27-3.29 (m, 1H); 2.91 (d, J = 6.1Hz, 1H); 1.34 (s, 3H); 1.07 (s, 3H).
実施例10Example 10
4-{トランス-2-[4-(3-フルオロフェニル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド、エナンチオマーA
段階A:4-(3-フルオロフェニル)-2-(トランス-2-フェニルシクロプロピル)ピリミジン
(トランス-2-フェニルシクロプロピル)ボロン酸(中間体1)(153mg、0.94mmol)のトルエン(4.75mL)及び水(0.25mL)の混合液中の溶液に、2-クロロ-4-(3-フルオロフェニル)ピリミジン(中間体A1)(131mg、0.63mmol)及び三塩基性リン酸カリウム(400mg、1.88mmol)を加え、反応混合物を窒素で脱酸素した。酢酸パラジウム(II)(28mg、0.13mmol)及びジ(1-アダマンチル)-n-ブチルホスフィン(90mg、0.25mmol)を加え、反応混合物を100℃に昇温させ、そして18時間攪拌した。反応混合物を酢酸エチル(10mL)で希釈し、水(5mL)及び飽和塩化ナトリウム水溶液(5mL)で洗浄し、脱水し(硫酸マグネシウム)、減圧下に濃縮した。残留物を酢酸エチル:ヘキサン-0:100から50:50の勾配で溶離を行うシリカゲルクロマトグラフィーによって精製し、標題化合物を得た。MS:m/z=291.2[M+H]。
4- {Trans-2- [4- (3-fluorophenyl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide, enantiomer A
Step A: Toluene (153 mg, 0.94 mmol) of 4- (3-fluorophenyl) -2- (trans-2-phenylcyclopropyl) pyrimidin (trans-2-phenylcyclopropyl) boronic acid (intermediate 1) (153 mg, 0.94 mmol) 2-Chloro-4- (3-fluorophenyl) pyrimidine (intermediate A1) (131 mg, 0.63 mmol) and tribasic phosphate in a solution in a mixture of 4.75 mL) and water (0.25 mL). Potassium (400 mg, 1.88 mmol) was added and the reaction mixture was deoxidized with nitrogen. Palladium (II) acetate (28 mg, 0.13 mmol) and di (1-adamantyl) -n-butylphosphine (90 mg, 0.25 mmol) were added, the reaction mixture was warmed to 100 ° C. and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water (5 mL) and saturated aqueous sodium chloride solution (5 mL), dehydrated (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: hexane-0: 100 to 50:50 to give the title compound. MS: m / z = 291.2 [M + H].
段階B:4-{トランス-2-[4-(3-フルオロフェニル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド、エナンチオマーA
4-(3-フルオロフェニル)-2-(トランス-2-フェニルシクロプロピル)ピリミジン(86mg、0.296mmol)のジクロロメタン(0.2mL)中溶液に、0℃でクロロスルホン酸(0.20mL、2.99mmol)を滴下し、反応混合物を30分間攪拌した。反応混合物を環境温度に昇温させ、そして30分間攪拌した。反応混合物を0℃に冷却し、氷水(5mL)に滴下し、層を分離した。水層をジクロロメタンで抽出し(5mLで3回)、合わせた有機抽出液を減圧下に濃縮した。残留物を1,4-ジオキサン(1.0mL)に溶かし、得られた溶液にアンモニア(7Mメタノール中溶液、0.5mL、3.5mmol)を加えた。反応混合物を15分間攪拌し、水(5mL)で希釈した。層を分離し、水層を酢酸エチルで抽出した(10mLで2回)。合わせた有機抽出液を水(10mL)及び飽和塩化ナトリウム水溶液(10mL)で洗浄し、脱水し(硫酸マグネシウム)、減圧下に濃縮した。残留物を酢酸エチル:エタノール:ヘキサン-3:1:96から57:19:24の勾配で溶離を行うシリカゲルクロマトグラフィーによって精製し、ラセミ体の標題化合物を得た。そのラセミ体を、メタノール:二酸化炭素-30:70で溶離を行うChiralPak OJ-Hカラムを用いるSFCによって分割した。第1の溶出主要ピークは4-{トランス-2-[4-(3-フルオロフェニル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド、エナンチオマーA、標題化合物であり、第2の溶出主要ピークは4-{トランス-2-[4-(3-フルオロフェニル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド、エナンチオマーBであった。MS:m/z=370.1[M+H]。1H NMR(600MHz、DMSO-d6):δ8.79(d、J=5.3Hz、1H)、8.08(d、J=7.7Hz、1H)、8.04(d、J=10.2Hz、1H)、7.93(d、J=5.3Hz、1H)、7.73(d、J=8.4Hz、2H)、7.64-7.58(m、1H)、7.45(d、J=8.4Hz、2H)、7.43-7.39(m、1H)、7.30(s、2H)、2.75-2.69(m、1H)、2.67-2.62(m、1H)、1.92-1.87(m、1H)、1.72-1.67(m、1H)。
Step B: 4- {trans-2- [4- (3-fluorophenyl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide, enantiomer A
4- (3-Fluorophenyl) -2- (trans-2-phenylcyclopropyl) pyrimidine (86 mg, 0.296 mmol) in a solution in dichloromethane (0.2 mL) at 0 ° C. with chlorosulfonic acid (0.20 mL, 2.99 mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes. The reaction mixture was warmed to ambient temperature and stirred for 30 minutes. The reaction mixture was cooled to 0 ° C. and added dropwise to ice water (5 mL) to separate the layers. The aqueous layer was extracted with dichloromethane (3 times at 5 mL) and the combined organic extracts were concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (1.0 mL) and ammonia (7M solution in methanol, 0.5 mL, 3.5 mmol) was added to the resulting solution. The reaction mixture was stirred for 15 minutes and diluted with water (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (twice at 10 mL). The combined organic extracts were washed with water (10 mL) and saturated aqueous sodium chloride solution (10 mL), dehydrated (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate: ethanol: hexane-3: 1: 96 to 57:19:24 to give the racemic title compound. The racemate was split by SFC using a CrystalPak OJ-H column elution with methanol: carbon dioxide-30:70. The first major elution peak is 4- {trans-2- [4- (3-fluorophenyl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide, enantiomer A, the title compound, and the second major elution peak. Was 4- {trans-2- [4- (3-fluorophenyl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide, enantiomer B. MS: m / z = 370.1 [M + H]. 1 1 H NMR (600 MHz, DMSO-d 6 ): δ8.79 (d, J = 5.3 Hz, 1H), 8.08 (d, J = 7.7 Hz, 1H), 8.04 (d, J = 10.2Hz, 1H), 7.93 (d, J = 5.3Hz, 1H), 7.73 (d, J = 8.4Hz, 2H), 7.64-7.58 (m, 1H), 7.45 (d, J = 8.4Hz, 2H), 7.43-7.39 (m, 1H), 7.30 (s, 2H), 2.75-2.69 (m, 1H), 2.67-2.62 (m, 1H), 1.92-1.87 (m, 1H), 1.72-1.67 (m, 1H).
実施例11Example 11
4-(トランス-2-{4-[5-(トリフルオロメチル)ピリジン-3-イル]ピリミジン-2-イル}シクロプロピル)ベンゼンスルホンアミド、エナンチオマーA
2-クロロ-4-(3-フルオロフェニル)ピリミジンに代えて2-クロロ-4-[5-(トリフルオロメチル)ピリジン-3-イル]ピリミジン(中間体11)を用いた以外は実施例10に記載の手順に実質的に従い、ラセミ体の標題化合物を得た。そのラセミ体を、メタノール:二酸化炭素-30:70で溶離を行うChiralPak AS-Hカラムを用いるSFCによって分割した。第1の溶出主要ピークは4-(トランス-2-{4-[5-(トリフルオロメチル)ピリジン-3-イル]ピリミジン-2-イル}シクロプロピル)ベンゼンスルホンアミド、エナンチオマーA、標題化合物であり、第2の溶出主要ピークは4-(トランス-2-{4-[5-(トリフルオロメチル)ピリジン-3-イル]ピリミジン-2-イル}シクロプロピル)ベンゼンスルホンアミド、エナンチオマーBであった。MS:m/z=421.0[M+H]。1H NMR(600MHz、DMSO-d6):δ9.68(s、1H)、9.16(s、1H)、8.90(s、1H)、8.88(d、J=5.2Hz、1H)、8.15(d、J=5.2Hz、1H)、7.74(d、J=8.2Hz、2H)、7.45(d、J=8.3Hz、2H)、7.30(s、2H)、2.79-2.74(m、1H)、2.73-2.67(m、1H)、1.95-1.89(m、1H)、1.76-1.69(m、1H)。
4- (Trans-2-{4- [5- (trifluoromethyl) pyridin-3-yl] pyrimidin-2-yl} cyclopropyl) benzenesulfonamide, enantiomer A
Example 10 except that 2-chloro-4- [5- (trifluoromethyl) pyridin-3-yl] pyrimidine (intermediate 11) was used instead of 2-chloro-4- (3-fluorophenyl) pyrimidine. Substantially following the procedure described in, the racemic title compound was obtained. The racemate was split by SFC using a CrystalPak AS-H column elution with methanol: carbon dioxide-30:70. The first major elution peak is 4- (trans-2- {4- [5- (trifluoromethyl) pyridin-3-yl] pyrimidin-2-yl} cyclopropyl) benzenesulfonamide, enantiomer A, title compound. The second major elution peak was 4- (trans-2- {4- [5- (trifluoromethyl) pyridin-3-yl] pyrimidin-2-yl} cyclopropyl) benzenesulfonamide, enantiomer B. rice field. MS: m / z = 421.0 [M + H]. 1 1 H NMR (600 MHz, DMSO-d 6 ): δ9.68 (s, 1H), 9.16 (s, 1H), 8.90 (s, 1H), 8.88 (d, J = 5.2 Hz) , 1H), 8.15 (d, J = 5.2Hz, 1H), 7.74 (d, J = 8.2Hz, 2H), 7.45 (d, J = 8.3Hz, 2H), 7 .30 (s, 2H), 2.79-2.74 (m, 1H), 2.73-2.67 (m, 1H), 1.95-1.89 (m, 1H), 1.76 -1.69 (m, 1H).
下記の表にある実施例を、当業者に公知の修正を加え、同様の変換の結果として記載若しくは製造されるように上記の実施例と同様にして製造した。必要な原料は、本明細書に記載されていたか、市販されていたか、文献で公知であったか又は当業者によって容易に合成された。一部の経路では直接保護基戦略を用いた。 The examples in the table below were made in the same manner as the above examples so that they would be described or manufactured as a result of similar conversions with modifications known to those of skill in the art. The required raw materials were described herein, were commercially available, were known in the literature, or were readily synthesized by one of ordinary skill in the art. Some routes used a direct protecting group strategy.
表EX-ATable EX-A
表EX-BTable EX-B
表EX-CTable EX-C
表EX-DTable EX-D
表EX-ETable EX-E
表EX-FTable EX-F
表EX-GTable EX-G
α7ニコチン性アセチルコリン受容体活性のポジティブアロステリック調節剤としての本発明による化合物の有用性を、当業界で公知の方法によって示すことができる。α7の直接活性化(作動作用)及びアセチルコリン誘発α7電流の増強を、次のようにして求めた。 The usefulness of the compound according to the present invention as a positive allosteric regulator of α7 nicotinic acetylcholine receptor activity can be demonstrated by methods known in the art. The direct activation (actuating action) of the α7 and the enhancement of the acetylcholine-induced α7 current were determined as follows.
自動パッチクランプ電気生理学機能アッセイ(アッセイA)
自動パッチクランプ電気生理学試験を、全細胞、群パッチ形態でIonFlux HT(Fluxion Biosciences Inc., San Francisco, CA)を用いて行った。試験化合物について、天然α7作動薬アセチルコリン存在下及び非存在下の両方でのα7ニコチン性アセチルコリン受容体の機能を調節する能力を評価した。ヒトRIC-3及びヒトα7の両方を安定に発現するHEK細胞系(PrecisION hnAChR α7/RIC-3, Eurofins Pharma, St. Charles, MO)を、175cm2三層組織培養フラスコで、10%加熱失活ウシ胎仔血清、1%非必須アミノ酸、0.625μg/mLピューロマイシン、及び400μg/mLジェネテシンを補充したDMEM/F-12増殖培地中で90%以下の密集度まで培養した。アッセイ直前に、最初に増殖培地を吸引し、ダルベッコリン酸緩衝生理食塩水で洗い、次にフラスコにAccutase (Innovative Cell Technologies, San Diego, CA)10mLを加え、そして37℃で5分間インキュベートすることで細胞を分離した。分離した細胞を、25mM HEPESを補充したCHO血清非含有培地40mLを加えることで回収し、50mL円錐管中で優しく揺らしてから、20分間後にパッチクランプアッセイを行った。回収後、小型卓上型遠心機で1000rpmで1分間遠心することで細胞をペレット化し;回収培地を吸引し、細胞を外部記録溶液(150mM NaCl、5mM KCl、2mM CaCl2、1mM MgCl2、10mM HEPES、12mMブドウ糖)に密度5.0×106細胞/mLまで再懸濁した。予め洗浄し、脱イオンH2OでプライミングしておいたIonFlux HT群パッチプレート上の細胞導入ウェルに細胞懸濁液を加えた。試験化合物をDMSOで連続希釈し、外部記録溶液に40μMアセチルコリンを加えて又は加えずに、外部記録溶液に最終試験濃度まで再懸濁させ;次に、試験化合物をIonFlux HT群パッチプレートに移した。内部記録溶液(110mM TrisPO4、28mM TrisBase、0.1mM CaCl2、2mM MgCl2、11mM EGTA、4mM MgATP)を、細胞及び試験化合物を負荷しておいたIonFlux HTパッチプレート上の内部記録溶液導入ウェルに加え、プレートをIonFlux HT装置に負荷した。プロトコールをIonFlux HTで行って細胞を捕捉し、細胞に分け(break into)、全細胞記録形態を確立し;実験期間にわたり、細胞を保持電位-60mVで電圧固定し、全ての実験を室温で実施し、IonFlux HT注入圧は溶液付与で約55hPa(8psi)であった。全細胞形態の確立時に、外部記録溶液を120秒間にわたり記録チャンバに潅流させ、次に40μMアセチルコリンを1秒間付与し、直ちに外部記録溶液で60秒間洗い落とした。40μMアセチルコリン誘発α7電流を、40μMアセチルコリンの存在下若しくは非存在下での引き続いての試験化合物効果を定量する基準となる電流応答とした。次に、試験化合物について、複数濃度でα7電流応答を誘発又は調節する能力を評価し;試験化合物の3種類の濃度を、記録当たりの用量を上昇させる手法で評価した。試験化合物作動薬活性を評価するため、外部記録溶液で希釈した試験化合物を、調べる試験化合物の最低濃度から出発して一連の濃度で58秒間付与し;58秒のうちの最初の20秒間、化合物付与期間はデータ収集掃引(期間20秒間)と同時とし、5,000サンプル/秒の速度で収集した。試験化合物ポジティブアロステリック調節剤活性を評価するため、58秒間の試験化合物のみ付与期間の直後に、40μMアセチルコリンを含む外部記録溶液で希釈した同じ濃度の試験化合物を1秒間付与し;そのようにして試験化合物及び天然受容体作動薬アセチルコリを同時付与し、試験化合物の増強効果を観察した。40μMアセチルコリンを含む外部溶液で希釈した試験化合物の前記1秒間の付与はデータ収集掃引(期間20秒間)と同時に行い、5,000サンプル/秒の速度で収集し、その後、外部記録溶液のみを42秒間付与した。この42秒間の外部記録溶液のみによる洗浄の後、一連の濃度での試験化合物の次の最大濃度を、前述のようにアセチルコリンの非存在下、次に存在下に付与し、前述のようにデータを収集した。試験化合物作動薬及びポジティブアロステリック調節剤活性を、濃度を3段階で上昇させながら評価した後実験を終了し、IonFlux HTデータ解析ソフトウェアを用いてリーク減算を行った。ピーク電流振幅及び曲線下面積(AUC)の両方を自社ソフトウェアを用いて各電流掃引について定量し、試験化合物効果を下記のように定量した。
Automatic patch clamp electrophysiological function assay (assay A)
Automatic patch clamp electrophysiological tests were performed in whole cell, group patch form using IonFlux HT (Fluxion Biosciences Inc., San Francisco, CA). The test compounds were evaluated for their ability to regulate the function of the α7 nicotinic acetylcholine receptor both in the presence and absence of the natural α7 agonist acetylcholine. The HEK cell line (PrecisION hnAChR α7 / RIC-3, Eurofins Pharma, St. Charles, MO) that stably expresses both human RIC-3 and human α7 was heated by 10% in a 175 cm 2 three-layer tissue culture flask. Live bovine fetal serum was cultured in DMEM / F-12 growth medium supplemented with 1% non-essential amino acids, 0.625 μg / mL puromycin, and 400 μg / mL Genetesin to a density of 90% or less. Immediately prior to the assay, first aspirate the growth medium, wash with Dulbeccoline buffered saline, then add 10 mL of Actase (Innovative Cell Technologies, San Diego, CA) to the flask and incubate at 37 ° C. for 5 minutes. The cells were isolated in. Separated cells were harvested by adding 40 mL of CHO serum-free medium supplemented with 25 mM HEPES, gently shaken in a 50 mL conical tube, and then patch clamp assay was performed 20 minutes later. After recovery, cells are pelleted by centrifuge at 1000 rpm for 1 minute in a small tabletop centrifuge; the recovery medium is aspirated and the cells are subjected to external recording solution (150 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEEPS). , 12 mM glucose) and resuspended to a density of 5.0 × 106 cells / mL. Cell suspensions were added to cell transfer wells on IonFlux HT group patch plates that had been previously washed and primed with deionized H2O . The test compound was serially diluted in DMSO and resuspended in the external recording solution with or without 40 μM acetylcholine to the final test concentration; then the test compound was transferred to the IonFlux HT group patch plate. .. Internal recording solution introduction wells loaded with cells and test compounds with internal recording solution (110 mM TrisPO 4 , 28 mM TrisBase, 0.1 mM CaCl 2 , 2 mM MgCl 2 , 11 mM EGTA, 4 mM MgATP). In addition, the plate was loaded onto the IonFlux HT device. The protocol was performed on IonFlux HT to capture cells and break into cells to establish whole cell recording morphology; cells were voltage-fixed at retention potential -60 mV over the experimental period and all experiments were performed at room temperature. However, the IonFlux HT injection pressure was about 55 hPa (8 psi) when the solution was applied. Upon establishment of whole cell morphology, external recording solution was perfused into the recording chamber for 120 seconds, then 40 μM acetylcholine was applied for 1 second and immediately washed off with external recording solution for 60 seconds. The 40 μM acetylcholine-induced α7 current was used as the reference current response to quantify the subsequent effect of the test compound in the presence or absence of 40 μM acetylcholine. The test compounds were then evaluated for their ability to elicit or regulate the α7 current response at multiple concentrations; three concentrations of the test compound were evaluated in a manner that increased the dose per record. Test Compounds To assess agonist activity, test compounds diluted in external recording solution are applied at a series of concentrations starting from the lowest concentration of test compound to be examined for 58 seconds; the first 20 seconds of 58 seconds, compound. The application period was the same as the data collection and sweep (period 20 seconds), and the data was collected at a rate of 5,000 samples / second. Test Compound To assess positive allosteric regulator activity, immediately after the 58 second test compound application period, the same concentration of test compound diluted with an external recording solution containing 40 μM acetylcholine was applied for 1 second; thus the test. The compound and the natural receptor agonist acetylcholine were simultaneously applied, and the enhancing effect of the test compound was observed. The 1 second application of the test compound diluted with an external solution containing 40 μM acetylcholine was performed simultaneously with the data acquisition sweep (duration 20 seconds) and collected at a rate of 5,000 samples / second, after which only the external recording solution was 42. Granted for seconds. After washing with this external recording solution only for 42 seconds, the next maximum concentration of the test compound at a series of concentrations was applied in the absence and then in the presence of acetylcholine as described above and the data as described above. Was collected. After evaluating the activity of the test compound agonist and the positive allosteric regulator while increasing the concentration in three steps, the experiment was terminated and leak subtraction was performed using IonFlux HT data analysis software. Both the peak current amplitude and the area under the curve (AUC) were quantified for each current sweep using our software, and the effect of the test compound was quantified as follows.
試験化合物作動薬活性を、次のように計算した。 The test compound agonist activity was calculated as follows.
%作動作用=(Y/X)×100
試験化合物増強物質活性を、次のように計算した。
% Acting action = (Y / X) × 100
The test compound enhancer activity was calculated as follows.
%強化=[(Z/X)×100]-100
X=40μMアセチルコリンによって誘発されるピーク電流振幅(又はAUC)
Y=外部記録溶液で希釈された試験化合物によって誘発されるピーク電流振幅(又はAUC)
Z=40μMアセチルコリンを含む外部記録溶液で希釈された試験化合物によって誘発されるピーク電流振幅(又はAUC)。
% Strengthening = [(Z / X) x 100] -100
Peak current amplitude (or AUC) induced by X = 40 μM acetylcholine
Y = peak current amplitude (or AUC) induced by the test compound diluted in external recording solution
Peak current amplitude (or AUC) induced by the test compound diluted with an external recording solution containing Z = 40 μM acetylcholine.
従って、40μMアセチルコリン単独の場合と同じ電流振幅を誘発した試験化合物は、100%の計算%作動作用を示すと考えられる。40μMアセチルコリン単独から誘発される電流の2倍の電流振幅を誘発した40μMアセチルコリンと同時付与した試験化合物は、計算%増強100%を示すと考えられ、それに対して40μMアセチルコリン単独と同じ電流振幅を誘発した40μMアセチルコリンと同時付与の試験化合物は全く増強を示さないと特徴付けられよう。 Therefore, it is believed that the test compound that elicited the same current amplitude as 40 μM acetylcholine alone exhibits 100% calculated% operative action. The test compound co-fed with 40 μM acetylcholine, which elicited twice the current amplitude induced by 40 μM acetylcholine alone, was considered to exhibit a calculated% enhancement of 100%, whereas it elicited the same current amplitude as 40 μM acetylcholine alone. The test compound co-fed with 40 μM acetylcholine will be characterized as showing no enhancement.
ピーク電流振幅又は曲線下面積(AUC)によって誘導される作動薬及び増強データをグラフ化し、レーベンバーグ-マーカートアルゴリズムに基づく4パラメータロジスティック適合を用いて適合させた。その場合、y=A+((B-A)/(1+((C/x)AD)))である。 Agonist and augmentation data induced by peak current amplitude or subcurve area (AUC) were graphed and fitted using a 4-parameter logistic fit based on the Lebenberg-Markart algorithm. In that case, y = A + ((BA) / (1+ ((C / x) AD))).
A=最小値
B=最大値
C=EC50
D=傾き
x=試験化合物濃度
y=%作動作用又は%増強
自動パッチクランプ電気生理学機能アッセイ(アッセイA)での本発明の特定化合物の効力データを、下記の表に示す。
D = Inclination x = Test Compound Concentration y =% Working or% Enhanced The efficacy data of the particular compound of the invention in the automated patch clamp electrophysiological function assay (assay A) is shown in the table below.
*A(EC50≦0.1μM);B(0.1μM<EC50≦0.5μM);C(0.5μM<EC50≦5μM);D(5μM<EC50≦50μM)と定義される効力 * Defined as A (EC 50 ≤ 0.1 μM); B (0.1 μM <EC 50 ≤ 0.5 μM); C (0.5 μM <EC 50 ≤ 5 μM); D (5 μM <EC 50 ≤ 50 μM) efficacy
自動パッチクランプ電気生理学機能アッセイ(アッセイA)での本発明の特定化合物の電気生理学EC50値を、下記の表に示す。
各種の上記及び他の特徴及び機能、又はそれらの代替形態を、望ましくは組み合わせて、多くの他の異なる系又は適用とすることが可能であることは明らかである。さらに、現時点で予想も予期もされていない各種の代替形態、修正形態、変形形態又は改善形態を、後に当業者により作られることが可能であり、それも添付の特許請求の範囲に包含されることが意図される。 It is clear that the various above and other features and functions, or alternative forms thereof, can preferably be combined into many other different systems or applications. In addition, various alternatives, modifications, variants or improvements that are not expected or expected at this time can be made later by one of ordinary skill in the art, which are also included in the appended claims. Is intended.
Claims (14)
[式中、
Xは、
であり、
Yは、4個の置換基であり、それぞれ独立にH、(C1-C4)アルキル、ハロゲン及びOHから選択され、ここで、前記アルキルは、1以上のハロゲン又はOHで置換されていても良く;
Aは、ピリジン、ピリミジンまたはフェニルであり、それぞれ、(C 1 -C 6 )アルキル、O(C 1 -C 6 )アルキル、NR 7 R 8 、(C 3 -C 6 )シクロアルキル、アリール、ヘテロアリール及び複素環から選択される1個のR基で置換され、ここで、それぞれは、独立にハロゲン、CF 3 、CN、(C 1 -C 4 )アルキル、(C=O)O(C 1 -C 4 )アルキル及びフェニルから選択される1以上の置換基で置換されていても良く;
R3は、H、ハロゲン、Si(CH3)3又は(C1-C4)アルキルであり、ここで、前記アルキルは、1以上のハロゲンで置換されていても良く;
R4は、H、ハロゲン又は(C1-C4)アルキルであり、ここで、前記アルキルは、1以上のハロゲンで置換されていても良く;
R5はH又は(C1-C4)アルキルであり;
R6はH又は(C1-C4)アルキルであり;
R7及びR8は、独立にH、(C 1 -C 6 )アルキル、(C 3 -C 6 )シクロアルキル、アリール、ヘテロアリール及び複素環から選択され、ここで、各アルキル、シクロアルキル、アリール、ヘテロアリール及び複素環は、独立にハロゲン及びフェニルから選択される1以上の置換基で置換されていても良い。]。 A compound having the formula I below or a pharmaceutically acceptable salt thereof.
[During the ceremony,
X is
And
Y is four substituents, each independently selected from H, (C1 - C4 ) alkyl, halogen and OH, where the alkyl is substituted with one or more halogens or OH. Also good;
A is pyridine, pyrimidine or phenyl, which are (C 1 - C 6 ) alkyl, O (C 1 - C 6 ) alkyl, NR 7 R 8 , (C 3 - C 6 ) cycloalkyl, aryl, hetero, respectively. Substituted with one R group selected from aryls and heterocycles, where each is independently halogen, CF 3 , CN, (C 1 - C 4 ) alkyl, (C = O) O (C 1 ). -C 4 ) May be substituted with one or more substituents selected from alkyl and phenyl ;
R 3 is an H, halogen, Si (CH 3 ) 3 or (C1 -C 4 ) alkyl, where the alkyl may be substituted with one or more halogens;
R4 is H, a halogen or a (C1- C4 ) alkyl, where the alkyl may be substituted with one or more halogens ;
R 5 is H or (C 1 -C 4 ) alkyl;
R 6 is H or (C 1 -C 4 ) alkyl;
R 7 and R 8 are independently selected from H, (C 1 - C 6 ) alkyl, (C 3 - C 6 ) cycloalkyl, aryl, heteroaryl and heterocycle, where each alkyl, cycloalkyl, Aryls, heteroaryls and heterocycles may be substituted with one or more substituents independently selected from halogens and phenyls. ] .
[式中、
Aは、ピリジン、ピリミジン及びフェニルから選択され、それぞれ、(C1-C6)アルキル、O(C1-C6)アルキル、NR7R8、(C3-C6)シクロアルキル、アリール、ヘテロアリール及び複素環から選択される1個のR基で置換され、ここで、それぞれは、独立にハロゲン、CF3、CN、(C1-C4)アルキル、(C=O)O(C1-C4)アルキル及びフェニルから選択される1以上の置換基で置換されていても良く;
R3はH又はSi(CH3)3であり;
R4はHであり;そして
R7及びR8は、独立にH、(C1-C6)アルキル、(C3-C6)シクロアルキル、アリール、ヘテロアリール及び複素環から選択され、ここで、各アルキル、シクロアルキル、アリール、ヘテロアリール及び複素環は、独立にハロゲン及びフェニルから選択される1以上の置換基で置換されていても良い。] A compound having the following formula or a pharmaceutically acceptable salt thereof.
[During the ceremony,
A is selected from pyridine, pyrimidine and phenyl, respectively, (C 1 -C 6 ) alkyl, O (C 1 -C 6 ) alkyl, NR 7 R 8 , (C 3 -C 6 ) cycloalkyl, aryl, respectively. Substituted with one R group selected from heteroaryls and heterocycles, where each is independently halogen, CF 3 , CN, (C 1 -C 4 ) alkyl, (C = O) O (C). 1 -C 4 ) May be substituted with one or more substituents selected from alkyl and phenyl;
R 3 is H or Si (CH 3 ) 3 ;
R 4 is H; and R 7 and R 8 are independently selected from H, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, aryl, heteroaryl and heterocycles, where Each alkyl, cycloalkyl, aryl, heteroaryl and heterocycle may be substituted with one or more substituents independently selected from halogens and phenyls. ]
R3がH又はSi(CH3)3であり;
R4がHであり;そして
R7及びR8が、独立にH、(C1-C6)アルキル、シクロペンチル及びフェニルから選択され、ここで、各アルキル、シクロペンチル及びフェニルは、独立にハロゲン及びフェニルから選択される1以上の置換基で置換されていても良い、式Iaを有する請求項6に記載の化合物又は薬学的に許容されるその塩。 A is selected from pyridine, pyrimidine and phenyl, respectively (C 1 -C 6 ) alkyl, O (C 1 -C 6 ) alkyl, NR 7 R 8 , cyclobutyl, cyclopentyl, phenyl, pyridinyl, morpholinyl, imidazolyl, pyrazolyl, respectively. , Oxaziazolyl, pyrrolidinyl, piperazinyl, triazolyl and tetrahydropyranyl substituted with one R group, where each is independently halogen, CF 3 , CN, (C 1 -C 4 ) alkyl, ( It may be substituted with one or more substituents selected from C = O) O (C1- C4 ) alkyl and phenyl;
R 3 is H or Si (CH 3 ) 3 ;
R 4 is H; and R 7 and R 8 are independently selected from H, (C1 - C 6 ) alkyl, cyclopentyl and phenyl, where each alkyl, cyclopentyl and phenyl are independently halogen and. The compound of claim 6 having formula Ia or a pharmaceutically acceptable salt thereof, which may be substituted with one or more substituents selected from phenyl.
4-{トランス-2-[2-(モルホリン-4-イル)ピリミジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
4-[トランス-2-(6-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド;
4-[トランス-2-(5-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド;
4-{トランス-2-[4-(プロパン-2-イル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(ピロリジン-1-イル)ピリジン-3-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[3-(5-メチル-1,2,4-オキサジアゾール-3-イル)フェニル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[2-(プロパン-2-イル)ピリジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
4-(1R,3R)-2,2-ジメチル-3-{4-[5-(トリフルオロメチル)ピリジン-3-イル]ピリミジン-2-イル}シクロプロピル]ベンゼンスルホンアミド;
4-{トランス-2-[4-(3-フルオロフェニル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-(トランス-2-{4-[5-(トリフルオロメチル)ピリジン-3-イル]ピリミジン-2-イル}シクロプロピル)ベンゼンスルホンアミド;
4-{トランス-2-[6-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[4-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[5-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-[トランス-2-(6-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド;
4-{トランス-2-[5-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[5-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[3-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(1H-ピラゾール-1-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(テトラヒドロ-2H-ピラン-4-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[4-(プロパン-2-イル)ピリジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-[トランス-2-(6-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド;
4-[トランス-2-(5-シクロペンチルピリジン-2-イル)シクロプロピル]ベンゼンスルホンアミド;
4-{2-[6-(プロパン-2-イル)ピリジン-3-イル]-3-(トリメチルシリル)シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(プロパン-2-イル)ピリダジン-3-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(プロパン-2-イル)ピラジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[5-(プロパン-2-イル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[5-(プロパン-2-イル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[4-(プロパン-2-イル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{(1R,3R)-2,2-ジフルオロ-3-[4-(3-フルオロフェニル)ピリミジン-2-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[2-(ジメチルアミノ)ピリミジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[2-(シクロペンチルアミノ)ピリミジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[2-(ベンジルアミノ)ピリミジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
tert-ブチル4-{4-[トランス-2-(4-スルファモイルフェニル)シクロプロピル]ピリミジン-2-イル}ピペラジン-1-カルボキシレート;
4-(トランス-2-{2-[(2,2-ジメチルプロピル)アミノ]ピリミジン-4-イル}シクロプロピル)ベンゼンスルホンアミド;
4-(トランス-2-{2-[メチル(フェニル)アミノ]ピリミジン-4-イル}シクロプロピル)ベンゼンスルホンアミド;
4-{トランス-2-[2-(ピロリジン-1-イル)ピリミジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
4-(トランス-2-{2-[(4-フルオロフェニル)アミノ]ピリミジン-4-イル}シクロプロピル)ベンゼンスルホンアミド;
4-[トランス-2-(2-フェニルピリミジン-4-イル)シクロプロピル]ベンゼンスルホンアミド;
4-(トランス-2-{2-[(2-フェニルエチル)アミノ]ピリミジン-4-イル}シクロプロピル)ベンゼンスルホンアミド;
4-{トランス-2-[2-(フェニルアミノ)ピリミジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[2-(プロパン-2-イル)ピリジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[2-(プロパン-2-イル)ピリジン-4-イル]シクロプロピル}ベンゼンスルホンアミド;
4-[トランス-2-(2-シクロブチルピリジン-4-イル)シクロプロピル]ベンゼンスルホンアミド;
4-{トランス-2-[4-(1H-イミダゾール-1-イル)フェニル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[3-(1H-1,2,4-トリアゾール-1-イル)フェニル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(プロパン-2-イル)ピリジン-3-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[5-(ピロリジン-1-イル)ピリジン-3-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(1H-ピラゾール-1-イル)ピリジン-3-イル]シクロプロピル}ベンゼンスルホンアミド;
4-{トランス-2-[6-(プロパン-2-イルオキシ)ピリジン-3-イル]シクロプロピル}ベンゼンスルホンアミド;及び
4-{トランス-2-[6-(2-シアノプロパン-2-イル)ピリジン-3-イル]シクロプロピル}ベンゼンスルホンアミド
からなる群から選択される化合物又は薬学的に許容されるその塩。 4- {Trans-2- [6- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [2- (morpholine-4-yl) pyrimidin-4-yl] cyclopropyl} benzenesulfonamide;
4- [Trans-2- (6-cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide;
4- [Trans-2- (5-cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide;
4- {Trans-2- [4- (Propane-2-yl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (pyrrolidin-1-yl) pyridin-3-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [3- (5-methyl-1,2,4-oxadiazole-3-yl) phenyl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [2- (Propane-2-yl) Pyridine-4-yl] cyclopropyl} benzenesulfonamide;
4- (1R, 3R) -2,2-dimethyl-3-{4- [5- (trifluoromethyl) pyridin-3-yl] pyrimidine-2-yl} cyclopropyl] benzenesulfonamide;
4- {Trans-2- [4- (3-fluorophenyl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide;
4- (Trans-2- {4- [5- (trifluoromethyl) pyridin-3-yl] pyrimidin-2-yl} cyclopropyl) benzenesulfonamide;
4- {Trans-2- [6- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [4- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [5- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- [Trans-2- (6-cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide;
4- {Trans-2- [5- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [5- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [3- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (1H-pyrazole-1-yl) pyridin-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (tetrahydro-2-H-pyran-4-yl) pyridin-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [4- (Propane-2-yl) Pyridine-2-yl] cyclopropyl} benzenesulfonamide;
4- [Trans-2- (6-cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide;
4- [Trans-2- (5-cyclopentylpyridin-2-yl) cyclopropyl] benzenesulfonamide;
4- {2- [6- (Propane-2-yl) Pyridine-3-yl] -3- (trimethylsilyl) cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (Propane-2-yl) pyridazine-3-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (Propane-2-yl) pyrazine-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [5- (Propane-2-yl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [5- (Propane-2-yl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [4- (Propane-2-yl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide;
4-{(1R, 3R) -2,2-difluoro-3- [4- (3-fluorophenyl) pyrimidin-2-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [2- (dimethylamino) pyrimidin-4-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [2- (cyclopentylamino) pyrimidin-4-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [2- (benzylamino) pyrimidin-4-yl] cyclopropyl} benzenesulfonamide;
tert-Butyl 4- {4- [trans-2- (4-sulfamoylphenyl) cyclopropyl] pyrimidine-2-yl} piperazine-1-carboxylate;
4- (Trans-2-{2-[(2,2-dimethylpropyl) amino] pyrimidin-4-yl} cyclopropyl) benzenesulfonamide;
4- (Trans-2- {2- [methyl (phenyl) amino] pyrimidin-4-yl} cyclopropyl) benzenesulfonamide;
4- {Trans-2- [2- (pyrrolidin-1-yl) pyrimidin-4-yl] cyclopropyl} benzenesulfonamide;
4- (Trans-2-{2-[(4-fluorophenyl) amino] pyrimidin-4-yl} cyclopropyl) benzenesulfonamide;
4- [Trans-2- (2-phenylpyrimidine-4-yl) cyclopropyl] benzenesulfonamide;
4- (Trans-2-{2-[(2-phenylethyl) amino] pyrimidin-4-yl} cyclopropyl) benzenesulfonamide;
4- {Trans-2- [2- (Phenylamino) pyrimidin-4-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [2- (Propane-2-yl) Pyridine-4-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [2- (Propane-2-yl) Pyridine-4-yl] cyclopropyl} benzenesulfonamide;
4- [Trans-2- (2-Cyclobutylpyridin-4-yl) cyclopropyl] benzenesulfonamide;
4- {Trans-2- [4- (1H-imidazol-1-yl) phenyl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [3- (1H-1,2,4-triazole-1-yl) phenyl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (Propane-2-yl) Pyridine-3-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [5- (pyrrolidin-1-yl) pyridin-3-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (1H-pyrazole-1-yl) pyridin-3-yl] cyclopropyl} benzenesulfonamide;
4- {Trans-2- [6- (Propane-2-yloxy) Pyridine-3-yl] cyclopropyl} benzenesulfonamide; and 4- {Trans-2- [6- (2-Cyanopropane-2-yl] ) Pyridine-3-yl] Cyclopropyl} A compound selected from the group consisting of benzenesulfonamides or pharmaceutically acceptable salts thereof.
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JP2010539188A (en) | 2007-09-17 | 2010-12-16 | アボット・ラボラトリーズ | N-phenyl-dioxo-hydropyrimidines useful as hepatitis C virus (HCV) inhibitors |
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US11793821B2 (en) | 2023-10-24 |
WO2018085170A1 (en) | 2018-05-11 |
EP3534889A1 (en) | 2019-09-11 |
US20210077511A1 (en) | 2021-03-18 |
JP2019533678A (en) | 2019-11-21 |
EP3534889A4 (en) | 2020-05-06 |
US20210196734A1 (en) | 2021-07-01 |
US11026958B2 (en) | 2021-06-08 |
EP3534889B1 (en) | 2022-04-06 |
CA3041331A1 (en) | 2018-05-11 |
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